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Volume 16 • 2021

Editor-in-Chief Peter O’Kane

Royal Bournemouth Hospital, Bournemouth, UK

Deputy Editors

Coronary

M Chadi Alraies

Structural

Detroit Medical Center, Detroit, MI Development

University Tor Vergata; Cardiac Cath Lab, San Gaudenzio Hospital, Italy

Angela Hoye

Castle Hill Hospital, Hull, UK

Development

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Nicolas M Van Mieghem Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands

Development

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University Hospital of Wales, Cardiff, UK

Statistical Editor Jufen Zhang

Anglia Ruskin University Medical School, Cambridge, UK

Editorial Board Mirvat Alasnag

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King Fahd Armed Forces Hospital, Jeddah, Saudi Arabia

Careggi University Hospital, Florence, Italy

Fernando Alfonso

Mauro Echavarría-Pinto

Hospital Universitario de La Princesa, Madrid, Spain

Giuseppe Andò

Azienda Ospedaliera Universitaria Policlinico “Gaetano Martino”Messina University Via Consolare Valeria, Italy

Hospital General ISSSTE Querétaro, Mexico

Eric Eeckhout

Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Gemma Figtree

Andrew Archbold

Royal North Shore Hospital, University of Sydney, Sydney, Australia

Eduardo Arias

Gosford Public Hospital, Gosford, NSW, Australia

Antonious Attallah

Swedish Heart and Vascular Institute, Seattle, WA, US

London Chest Hospital, Barts Health NHS Trust, London, UK National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico Ascension St. John Hospital, Detroit, MI, US

Rodrigo Bagur

London Health Sciences Centre, London, Ontario, Canada

Marco Barbanti

Ferrarotto Hospital, Catania, Italy

Jonathan Byrne

King’s College Hospital, London, UK

Antonio Colombo

EMO Centro Cuore Columbus, Milan, Italy

Pierluigi Costanzo

Royal Papworth Hospital, Cambridge, UK

Nick Curzen

University Hospital Southampton NHS Trust, Southampton, UK, and British Cardiovascular Intervention Society

Tom Ford

Sameer Gafoor

Philippe Garot

Won Keun Kim

Kerckhoff Heart Center, Bad Nauheim, Germany

Tim Kinnaird

University Hospital of Wales, Cardiff, UK

Ajay Kirtane

Azeem Latib

Rigshospitalet – Copenhagen University Hospital, Copenhagen, Denmark

Montefiore Medical Center, New York, NY, US

Didier Locca

Lausanne University Hospital, Lausanne, Switzerland

Mamas A Mamas

University of Keele, Keele, Staffordshire, UK

Hannah McConkey

Mario Iannaccone

Thomas Modine

Raban Jeger

Kathleen E Kearney

University of Washington Heart Institute, Seattle, WA, US

Simon Kennon

Barts Heart Centre, St Bartholomew’s Hospital, London, UK

Jaffar Khan

National Heart, Lung and Blood Institute, Washington, DC, US

Alexander Sedaghat

University of Bonn, Bonn, Germany

St Thomas’ Hospital, London, UK

University Hospital Basel, Switzerland

Fadi J Sawaya

American University of Beirut Medical Center, Beirut, Lebanon

Columbia University Medical Center and New York-Presbyterian Hospital, New York, NY, US

Institut Cardiovasculaire Paris-Sud – Hôpital Privé Jacques Cartier (Ramsay Générale de Santé), Massy, France San Giovanni Bosco Hospital, ASL Città di Torino, Italy

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Galway University Hospitals, Galway, Ireland

Roxana Mehran

Mount Sinai Hospital, New York, NY, US

Lars Søndergaard

James Spratt

St George’s University Hospital NHS Trust, London, UK

Gregg W Stone

Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, US

Corrado Tamburino

Ferrarotto & Policlinico Hospital and University of Catania, Catania, Italy

Luca Testa

Darren Mylotte

Department of Cardiology, IRCCS Policlinico San Donato, San Donato Milanese, Italy

Sandeep Nathan

University Hospital Düsseldorf, Düsseldorf, Germany

CHRU de Lille, Lille, France Galway University Hospitals, Galway, Ireland University of Chicago Medicine, Section of Cardiology, Chicago, Illinois, US

Elmir Omerovic

Sahlgrenska University Hospital, Gothenburg, Sweden

Crochan J O’Sullivan Triemli Hospital, Zurich, Switzerland

Verena Veulemans Renu Virmani

CVPath Institute, MD, US

Simon Walsh

Belfast Health and Social Care Trust, Belfast, UK

Nina C Wunderlich

Cardiovascular Center Darmstadt, Darmstadt, Germany

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Contents Volume 7 • 2021 Exercise Right Heart Catheterisation in Cardiovascular Diseases: A Guide to Interpretation and Considerations in the Management of Valvular Heart Disease Felipe H Valle, Basma Mohammed, Stephen P Wright, Robert Bentley, Neil P Fam and Susanna Mak DOI: https://doi.org/10.15420/icr.2020.17

Balloon Pulmonary Angioplasty: State of the Art

John G Coghlan, Alexander MK Rothman and Stephen P Hoole DOI: https://doi.org/10.15420/icr.2020.14

Extended Statement by the British Cardiovascular Intervention Society President Regarding Transcatheter Aortic Valve Implantation

Philip MacCarthy, Dave Smith, Douglas Muir, Daniel Blackman, Mamta Buch, Peter Ludman, Clare Appleby, Nick Curzen, David Hildick-Smith, Neal Uren, Mark Turner, Uday Trivedi and Adrian Banning DOI: https://doi.org/10.15420/icr.2021.02

Shifting Paradigms and Financing a Revolution: Providing Transcatheter Valves in the Public Health System. A View from Aotearoa New Zealand Cameron McAlister and David Smyth DOI: https://doi.org/10.15420/icr.2020.03

Frailty Scores and Their Utility in Older Patients with Cardiovascular Disease

Kenneth Jordan Ng Cheong Chung, Chris Wilkinson, Murugapathy Veerasamy and Vijay Kunadian DOI: https://doi.org/10.15420/icr.2020.18

Contemporary Management of Isolated Ostial Side Branch Disease: An Evidence-based Approach to Medina 001 Bifurcations Suleiman Suleiman, JJ Coughlan, George Touma and Richard Szirt DOI: https://doi.org/10.15420/icr.2020.30

Transcatheter Mitral Valve Replacement: Current Evidence and Concepts

Ozan M Demir, Mhairi Bolland, Jonathan Curio, Lars Søndergaard, Josep Rodés-Cabau, Simon Redwood, Bernard Prendergast, Antonio Colombo, Mei Chau and Azeem Latib DOI: https://doi.org/10.15420/icr.2020.25

Minimally Invasive Coronary Revascularisation Surgery: A Focused Review of the Available Literature

Karel M Van Praet, Markus Kofler, Timo Z Nazari Shafti, Alaa Abd El Al, Antonia van Kampen, Andrea Amabile, Gianluca Torregrossa, Jörg Kempfert, Volkmar Falk, Husam H Balkhy and Stephan Jacobs DOI: https://doi.org/10.15420/icr.2021.05

Moderate Aortic Stenosis: What is it and When Should We Intervene?

Sveeta Badiani, Sanjeev Bhattacharyya, Nikoo Aziminia, Thomas A Treibel and Guy Lloyd DOI: https://doi.org/10.15420/icr.2021.04

What an Interventionalist Needs to Know About MI with Non-obstructive Coronary Arteries Robert Sykes, Daniel Doherty, Kenneth Mangion, Andrew Morrow and Colin Berry DOI: https://doi.org/10.15420/icr.2021.10

Haemodynamic Interplay Between Concomitant Left Ventricular Outflow Tract Obstruction and Aortic Stenosis Priya Bansal, Hamza Lodhi, Adithya Mathews, Anand Desai, Ramez Morcos, Brijeshwar Maini and Houman Khalili DOI: https://doi.org/10.15420/icr.2020.36

Predictors of In-Hospital Outcomes among Octogenarians with Acute ST-elevation Myocardial Infarction at the Philippine Heart Center Emily Mae L Yap and Alexander A Tuazon DOI: https://doi.org/10.15420/icr.2021.16.PO1

Radiation Dose in Coronary Angiography and Percutaneous Coronary Intervention: Establishment of Diagnostic Reference Levels at the Philippine Heart Center Emily Mae L Yap, Livy P Magno, Christopher A Macaraeg, Gilbert E Pedroso, Aeron G Ramos, Mardy Zaldess S Cruz, Alexander A Tuazon, Ronaldo H Estacio, Ramoncito B Tria DOI: https://doi.org/10.15420/icr.2021.16.PO2

A Staged Hybrid Approach to an Aberrant Right Subclavian Artery with Symptomatic Kommerell’s Diverticulum Krystal Dinh, Lucy Manuel, Kalpa Perera and Thomas Daly DOI: https://doi.org/10.15420/icr.2021.16.PO3

Endovascular Treatment of a Large Iatrogenic Popliteal Arteriovenous Fistula Krystal Dinh, Andrew Ying, Rafid Al-Asady and Mauro Vicaretti DOI: https://doi.org/10.15420/icr.2021.16.PO4

Vascular Tracheobronchial Compression Syndrome Secondary to Contained Ruptured Thoracic Aortic Aneurysm Krystal Dinh, Lucy Manual and Mauro Vicaretti DOI: https://doi.org/10.15420/icr.2021.16.PO5

Three Years’ Libyan Experience in Congenital Heart Disease Interventions M Madany, S Rahouma, A Khazmi, R AL Fitouri and S Rahouma DOI: https://doi.org/10.15420/icr.2021.16.PO6

www.CFRjournal.com

Contents

Single Operator Observational Study of Incidence of Pocket Site Infection and Safety of Absorbable Sutures for Pocket Closure of Cardiac Implantable Electronic Devices Inderjeet Singh Monga

DOI: https://doi.org/10.15420/icr.2021.16.PO7

Single Centre Observational Study on Clinical Profile and Optical Coherence Tomography-guided Management Strategy for Patients with Young Acute Coronary Syndrome Inderjeet Singh Monga, Anil Kumar, R Girish and AK Sood DOI: https://doi.org/10.15420/icr.2021.16.PO8

Clinical Experience of Percutaneous Coronary Intervention for Severely Calcified Coronary Artery Lesions with Orbital Atherectomy System Jumpei Koike, Yoshihiro Iwasaki, Toshinori Ko, Atsushi Funatsu, Tomoko Kobayashi and Shigeru Nakamura DOI: https://doi.org/10.15420/icr.2021.16.PO9

Patient Radiation Exposure During Primary Percutaneous Coronary Intervention in Acute ST-elevation Myocardial Infarction at the Philippine Heart Center Emily Mae L Yap, Christopher Macaraeg, Richard Ayuson, Alexander Tuazon, Ronaldo Estacio and Ramoncito Tria DOI: https://doi.org/10.15420/icr.2021.16.PO10

Giant Abdominal Aortic Aneurysm: Radiographic Features of Impending Rupture in an Atypical Presentation Aman B Williams and Lauren G Lax

DOI: https://doi.org/10.15420/icr.2021.16.PO11

Mistral Tricuspid Regurgitation Echocardiography CoreLab Analysis Results Yan Topilsky, Dana Yaron and Meytal Bork DOI: https://doi.org/10.15420/icr.2021.16.PO12

Functionally Complete Coronary Revascularisation in Patients Presenting with ST-elevation MI and Multivessel Coronary Artery Disease Luigi Di Serafino, Fabio Magliulo and Giovanni Esposito DOI: https://doi.org/10.15420/icr.2020.28

Advanced Cardiac Interventions During Pregnancy: A Personal Perspective Angela HEM Maas

DOI: https://doi.org/10.15420/icr.2020.12

Patient-specific Computer Simulation: An Emerging Technology for Guiding the Transcatheter Treatment of Patients with Bicuspid Aortic Valve Cameron Dowling, Robert Gooley, Liam McCormick, Sami Firoozi and Stephen J Brecker DOI: https://doi.org/10.15420/icr.2021.09

Factors Influencing Stent Failure in Chronic Total Occlusion Coronary Intervention Kalaivani Mahadevan, Claudia Cosgrove and Julian W Strange DOI: https://doi.org/10.15420/icr.2021.03

Pre-dilation and Post-dilation in Transcatheter Aortic Valve Replacement: Indications, Benefits and Risks

Angela McInerney, Rafael Vera-Urquiza, Gabriela Tirado-Conte, Luis Marroquin, Pilar Jimenez-Quevedo, Iván Nuñez-Gil, Eduardo Pozo, Nieves Gonzalo, Jose Alberto de Agustín, Javier Escaned, Antonio Fernández-Ortiz, Carlos Macaya and Luis Nombela-Franco DOI: https://doi.org/10.15420/icr.2020.35

Is This the Prime Time for Transradial Access Left Ventricular Endomyocardial Biopsy?

Zaccharie Tyler, Oliver P Guttmann, Konstantinos Savvatis, Daniel Jones and Constantinos O’Mahony DOI: https://doi.org/10.15420/icr.2021.20

The Impact of Calcium on Chronic Total Occlusion Management

Claudia Cosgrove, Kalaivani Mahadevan, James C Spratt and Margaret McEntegart DOI: https://doi.org/10.15420/icr.2021.01

Cardiovascular Imaging and Intervention Through the Lens of Artificial Intelligence Karthik Seetharam, Sirish Shrestha and Partho P Sengupta DOI: https://doi.org/10.15420/icr.2020.04

What an Interventionalist Needs to Know About INOCA Daniel Tze Yee Ang and Colin Berry DOI: https://doi.org/10.15420/icr.2021.16

Advances in the Post-coronary Artery Bypass Graft Management of Occlusive Coronary Artery Disease Mohammed Shamim Rahman, Ruben de Winter, Alex Nap and Paul Knaapen DOI: https://doi.org/10.15420/icr.2021.12

Invasive Haemodynamic Assessment Before and After Left Ventricular Assist Device Implantation: A Guide to Current Practice Jesus Gonzalez and Paul Callan

DOI: https://doi.org/10.15420/icr.2021.13

Structural

Exercise Right Heart Catheterisation in Cardiovascular Diseases: A Guide to Interpretation and Considerations in the Management of Valvular Heart Disease Felipe H Valle ,1,2 Basma Mohammed,3 Stephen P Wright,1 Robert Bentley,1,4 Neil P Fam2 and Susanna Mak1 1. Division of Cardiology, Mount Sinai Hospital/University Health Network, Toronto, Canada; 2. Division of Cardiology, St Michael’s Hospital/ University of Toronto, Toronto, Canada; 3. Division of Internal Medicine, University of Toronto, Toronto, Canada; 4. Faculty of Kinesiology and Physical Education, University of Toronto, Toronto, Canada

Abstract

The use of exercise right heart catheterisation for the assessment of cardiovascular diseases has regained attention recently. Understanding physiologic haemodynamic exercise responses is key for the identification of abnormal haemodynamic patterns. Exercise total pulmonary resistance >3 Wood units identifies a deranged haemodynamic response and when total pulmonary resistance exceeds 3 Wood units, an exercise pulmonary artery wedge pressures/cardiac output slope >2 mmHg/l/min indicates the presence of underlying exercise-induced pulmonary hypertension related to left heart disease. In the evolving field of transcatheter interventions for valvular heart disease, exercise right heart catheterisation may objectively unmask symptoms and underlying haemodynamic abnormalities. Further studies are needed on the use of the procedure to inform the selection of patients who might receive the most benefit from transcatheter interventions for valvular heart diseases.

Keywords

Haemodynamics, exercise, cardiac catheterisation, valvular heart disease; pulmonary hypertension, transcatheter cardiac interventions Disclosure: The authors have no conflicts of interest to declare. Received: 31 May 2020 Accepted: 1 September 2020 Citation: Interventional Cardiology Review 2021;16:e01. DOI: https://doi.org/10.15420/icr.2020.17 Correspondence: Susanna Mak, Division of Cardiology, Mount Sinai Hospital, Room 18–365, 600 University Ave, Toronto, Ontario M5G 1X5, Canada. E: susanna.mak@sinaihealthsystem.ca Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Exercise is considered a physiologic and clinically relevant provocative manoeuvre to assess the function of the cardiovascular system. Comprehensive assessment of cardiac performance during exercise may reveal contributory pathophysiological responses when someone has exercise intolerance. Measures of functional capacity and cardiac performance during exercise and the detection of exercise-induced pulmonary hypertension may provide prognostic information in the setting of established cardiovascular disorders. Exercise right heart catheterisation provides an opportunity to identify haemodynamic phenotypes that reflect a reduction in pulmonary vascular and/or cardiac function, which may not be evident when the patient is at rest. The differentiation of these two pathophenotypes is a key element of exercise right heart catheterisation. Haemodynamic response patterns to exercise may also assist in assessing the severity of valvular heart disease, which can help to improve the management of these conditions. The objective of this review is to discuss the diagnostic contribution of exercise right heart catheterisation in cardiovascular disease. It will address methodological considerations of exercise right heart catheterisation before discussing ‘normal’ invasive cardiopulmonary responses during exercise – an important contextual framework required for identifying and understanding pathophysiological abnormalities. It will

then address the implications of exercise right heart catheterisation to improve diagnosis and treatment in valvular heart diseases.

How to Perform Exercise Right Heart Catheterisation

Exercise right heart catheterisation is more ergonomic when upper body venous access is used to place a multi-lumen pulmonary artery catheter which allows the lower body to be tested using a cycle ergometer. The safety profile of non-invasive exercise stress testing is beyond the scope of this review. However, the relatively small risk of complications associated with right heart catheterisation should be discussed with the patient so they are able to give their informed consent to the procedure.1 Since the majority of complications of right heart catheterisations are related to vascular access, our institution has chosen ultrasound-guided upper extremity venous access as our standard vascular venous access site so we can mitigate those risks, facilitate exercise and potentially improve the patient’s comfort. Once vascular venous access is secured, a balloon-tipped fluid-filled catheter is positioned in the pulmonary artery under fluoroscopic guidance and diagnostic right heart catheterisation is performed at rest. Heterogeneous procedural practices are encountered for the performance of exercise after initial right heart catheterisation. Supine exercise using a

A Guide to Exercise Right Heart Catheterisation Figure 1: Relationship Between Exercise Mean Pulmonary Artery Pressure and Cardiac Output LHD

Controls

PVD

pressure and PAWP during exercise, a phenomenon that is maybe due to age-related increases in ventricular-vascular stiffness.7 Notably, changes in flow are associated with changes in hydraulic pressure modelled on principles of hydraulic pumps.8–11 Therefore, evaluations of pulmonary and PAWP responses to exercise may be best described by pressure-flow relationships. Two pressure-flow relationships that identify the presence of pulmonary hypertension, and the possibility of left heart disease will now be discussed.

Historical healthy volunteers

60 TPR=3WU

MPAP mmHg

The Mean Pulmonary Artery Pressure/ Cardiac Output Response to Exercise

30 20 10 0

15 CO/l/min

Although exercise total pulmonary resistance >3 WU differentiated the diseased and non-diseased groups, pulmonary vascular disease and left heart disease could not be differentiated with this metric. CO = cardiac output; LHD = left heart disease; MPAP = mean pulmonary artery pressure; PVD = pulmonary vascular disease; TPR = total pulmonary resistance; WU = Wood units. Source: Herve et al. 2015.15 Used with permission from European Respiratory Society.

table-mounted ergometer is easy to use, particularly for severely compromised patients but limits ambulatory activity, whereas upright or semi-upright positions avoid this but require the patient to be transferred from the catheterisation table.2,3 In our centre, we have adopted the semiupright position (30–45º head-up tilt), using a reclining table-cycle ergometer. After supine right heart catheterisation, patients are transferred to the cycle ergometer and pressure transducers are zeroed at the midaxillary level.4 Since vascular tone and preload conditions change when the upright/semi-upright position is adopted, we suggest that right atrium, pulmonary artery pressures and pulmonary artery wedge pressures (PAWP) and cardiac output (CO) are recorded in the upright/semi-upright position before exercise, and the measurement is performed in the same way at rest as they are during exercise.4,5 Our laboratory uses a submaximal exercise protocol to mitigate interferences in haemodynamic waveforms caused by large respiratory swings. We also use the average pressure measurements from >2 respiratory cycles in preference to end-expiratory measurements. When measuring CO during exercise, we choose from the thermodilution technique and the direct Fick method, which have both been validated for this purpose and the choice is made by considering operator expertise, exercise protocol in use and equipment availability.6 Arterial blood pressure – measured invasively or non-invasively – and heart rate are also monitored throughout the test.

Normal Cardiopulmonary Haemodynamic Responses to Exercise

Understanding the normal haemodynamic response pattern to exercise in healthy people is particularly relevant for the interpretation of exercise right heart catheterisation findings to discriminate between health and disease phenotypes. The interpretation of haemodynamic responses to exercise needs to take in consideration findings from data derived from studies in healthy people. Several factors influence the pulmonary and PAWP responses to exercise, which prevents there being single threshold values that define physiologic haemodynamic responses. Ageing is related to higher pulmonary

Until the 4th World Symposium on Pulmonary Hypertension, which took place in Dana Point, California in 2008, diagnostic criteria for pulmonary hypertension included haemodynamic thresholds both at rest – mean pulmonary artery pressure (MPAP) >25 mmHg – or during exercise (MPAP >30 mmHg).7 Although MPAP normally increases with CO during exercise, lack of uniformity in exercise stimulus and intensity and uncertainty as to the range of physiologic responses made it challenging to establish single threshold values for the diagnosis of disease. At the time, there was increasing evidence to suggest that age is a particular determinant of higher MPAP values in response to exercise, exceeding 30 mmHg in many healthy subjects.12 This prompted the removal of an exercise-induced pulmonary hypertension definition.13 Further prospective data and an additional systematic review including contemporary data from our laboratory confirmed that MPAP either after the onset of exercise or with escalating work rates is higher among older people.12–14 Recent work has refined the understanding of the relationship between increases in MPAP and CO during exercise. Disproportionate increases in MPAP relative to CO augmentation during exercise may represent either a failure of the normal decrease in pulmonary vascular resistance (PVR) with exercise, excessive upstream pressure transmission from the left atrium, or a combination.2,8 Adjusting MPAP values to CO, a variable known as total pulmonary resistance (TPR), is gaining acceptance for detection of abnormalities due to underlying pulmonary vascular or left-heart dysfunction.15,16 Herve et al. demonstrated in a cohort of 169 participants without pulmonary hypertension at rest, that applying a total pulmonary resistance cut-off of 3 WU on exercise holds 96% accuracy to differentiate healthy from deranged phenotypes (Figure 1). Moreover, using such criteria, the positive predictive value for the detection of diseased states was 100%.15 Similar results were found by Kovacs et al., who applied these criteria retrospectively and noted that the false positive rate for healthy subjects decreased from nearly 14% when employing a single point MPAP threshold > 30 mmHg with exercise to less than 3% when employing TPR slope.17

The Pulmonary Artery Pressure/Cardiac Output Response to Exercise

As discussed above for MPAP, recommendations for a single threshold value of the PAWP response to exercise are confounded by the complexity of physiologic responses. PAWP responses are linked to MPAP and are similarly influenced by age and also by exercise duration.7,18 In a study that included 62 healthy subjects divided by age groups, Wolsk et al. showed steeper increases in PAWP with exercise in older people and, importantly, CO augmentation during exercise was attenuated in older subjects compared with younger ones.7 These findings appear to show that higher PAWP responses during exercise are associated with physiologic ageing of the cardiac chamber function. Prospective data from our laboratory demonstrate that PAWP may increase precipitously shortly after the onset of exercise in older adults, with subsequent decline in values as exercise is sustained over minutes, reinforcing the importance of considering exercise

INTERVENTIONAL CARDIOLOGY REVIEW Access at: www.ICRjournal.com

A Guide to Exercise Right Heart Catheterisation Figure 2: Pulmonary Artery Wedge Pressures–Cardiac Output Relationship in Healthy Subjects A 4

∆PAWP/∆CO (mmHg/l/min)

Men Women

B Mean: 1.2 ± 0.76 mmHg/l/min

Mean: 0.43 ± 0.40 mmHg/l/min

–1

Mean: 1.3 ± 0.88 mmHg/l/min

Mean: 0.45 ± 0.54 mmHg/l/min

–1 Sustained light

Sustained moderate

Sustained light

Sustained moderate

Comparison of the change in PAWP per change in CO from control between sustained light and sustained moderate exercise in men (A) and women (B). CO = cardiac output; PAWP = pulmonary artery wedge pressures. Source: Esfandiari et al. 2017.18 Used with permission from Wolters Kluwer Health.

duration for the appraisal of PAWP response to exercise.12,18 Systematic reviews performed by our laboratory and by Kovacs et al. further endorse the association of age with higher PAWP responses during exercise, and can exceed 20 mmHg and even 25 mmHg both previously suggested cut-off values for the detection of heart failure with preserved ejection fraction (HFpEF) during exercise right heart catheterisation.7,12,14,18,19 The challenges of identifying a single upper limit threshold have prompted evaluation of the PAWP/CO relationship as a more comprehensive differentiation between physiologic and pathologic PAWP responses to exercise. In a study that included exercise right heart catheterisation among 36 healthy volunteers, our laboratory demonstrated that the slope between PAWP/CO does not exceed 2 mmHg/l/min during submaximal exercise performance.18 Importantly, in order to obtain steady-state flow measurements, CO measurements were performed after 3 minutes of exercise at fixed work rates (Figure 2). Despite a disparate exercise protocol, our findings were replicated in a study from Eisman et al. in which maximal exercise tests with incremental ramp protocols were used: exercise PAWP/CO slope ≤2 mmHg/l/min differentiated controls from those with HFpEF and identified patients with improved event-free survival from heart failure.20 This study also demonstrated greater exercise capacity and ventilatory efficiency in people with a lower PAWP/CO slope.

Interpretation and Indications for Exercise Right Heart Catheterisation

Right heart catheterisation is recommended to confirm the diagnosis of pulmonary hypertension to support treatment decisions. Clinical scenarios include the diagnosis of pulmonary arterial hypertension (PAH) for which pulmonary vasodilator therapy may be prescribed, to assess the risk of graft failure in patients with left heart disease undergoing evaluation of candidacy for cardiac transplantation, and to assess the severity of structural heart disease such as congenital cardiac shunts, or valvular heart lesions, particularly when non-invasive imaging is inconclusive. Pursuing a diagnosis of PAH illustrates some of the limitations of haemodynamic assessment in the resting supine state. Identifying patients who are eligible for treatment depends on showing evidence of pre-capillary pulmonary hypertension, defined as MPAP >20 mmHg and

PAWP <15 mmHg and PVR >3 WU. However, the current population of patients with PAH is older than previously considered and a proportion has a high prevalence of cardiovascular risk factors.21 As such, this population will overlap with patients at risk of abnormal left heart filling pressures due to left ventricular (LV) and systemic vascular stiffening and LV diastolic impairment. It may be challenging to differentiate pre-capillary pulmonary hypertension from post-capillary pulmonary hypertension, also known as pulmonary hypertension, related to left heart disease (PH-LHD). Differentiating PAH from PH-LHD is essential as specific therapy improves clinical outcomes in PAH but is potentially deleterious in PH-LHD.22–27 Borlaug et al. and others have demonstrated the ability of exercise right heart catheterisation to identify patients with dyspnoea and normal resting haemodynamics to reveal abnormal PAWP responses, employing point measurements that exceed threshold values. Among patients with PH present at rest, exercise may similarly reveal or clarify the dominant mechanisms contributing to PH. In our current practice, pressure-flow relationships are considered for the MPAP and the PAWP. The combination of an abnormal MPAP/CO relationship (>3 mmHg/l/min) and a PAWP/CO slope <2 mmHg/l/min suggests that the central derangement lies at the level of the pulmonary vasculature, which can be helpful when the PAWP at rest is in a borderline range. Alternatively, concordantly abnormal behaviour of both the PAWP/CO slope (>2 mmHg/l/min) and the MPAP/CO relationship may suggest that elevated pulmonary pressures are entirely driven by left heart filling pressures. In our pulmonary hypertension programme, exercise right heart catheterisation can support clinical decisions regarding administration of pulmonary vasodilator therapy. However, several questions remain unanswered and future research is directed at understanding whether decision-making based on exercise right heart catheterisation affects clinical outcomes or predicts a response to treatment. Another area of research relates to whether patterns of MPAP and PAWP based on exercise changes in CO may elucidate the contribution of pulmonary vascular disease in the presence of PH-LHD.

Rationale for the Use of Exercise Right Heart Catheterisation Before Valvular Interventions

The field of valvular heart diseases has substantially evolved in recent years, with tremendous progress in percutaneous interventional

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A Guide to Exercise Right Heart Catheterisation Table 1: Summary of Potential Applications for Exercise Right Heart Catheterisation in the Assessment of Valvular Heart Diseases Aortic Stenosis Exercise right heart catheterisation may be used for the identification of exercise pulmonary hypertension, particularly in asymptomatic patients with non-diagnostic stress echocardiography. In patients with moderate or severe asymptomatic AS, the correlation between pulmonary vascular and left-sided filling pressures in relation to flow responses may be further understood with the use of exercise right heart catheterisation.

Mitral Stenosis Exercise right heart catheterisation, preferably combined with Doppler echocardiography, may be used when discrepancies between mitral stenosis severity and symptoms are encountered. In asymptomatic patients, exercise right heart catheterisation may demonstrate the presence of severe exercise-induced pulmonary hypertension.

Mitral Regurgitation In asymptomatic patients with primary MR, exercise right heart catheterisation may be used for the identification of exercise pulmonary hypertension. Exercise right heart catheterisation may be used when discrepancies between MR severity and symptoms are encountered. In patients with secondary MR, the correlations between MR worsening, pulmonary vasculature, left-sided filling pressures and flow responses at exercise may be further understood with the use of exercise right heart catheterisation.

Tricuspid Regurgitation In patients with tricuspid regurgitation, exercise right heart catheterisation may be used for the assessment of right ventricular systolic function and right ventricular contractile reserve. AS = aortic stenosis; MR = mitral regurgitation.

techniques for valvular heart diseases. As the indications for percutaneous interventions expand to populations with moderate symptoms, it may be useful to have additional evaluations that may help to select candidates most likely to benefit from the procedure. In this setting, exercise right heart catheterisation may objectively unmask the occurrence of symptoms and underlying haemodynamic abnormalities, particularly in patients with vague, non-specific symptoms and in those in which the correlation between decreased functional capacity and the severity of underlying valvular heart disease assessed by echocardiography is unclear. The available data on exercise right heart catheterisation applications in heart valve diseases is summarised in Table 1. Currently, there is remarkably limited data on the role of exercise right heart catheterisation in the setting of aortic regurgitation, pulmonic valve disease or tricuspid stenosis and these topics are not addressed.

Aortic Stenosis

Aortic stenosis (AS) affects one in 20 people aged over 65 years, the prevalence of AS increases with age and it is currently the most common primary valve disease leading to surgical or transcatheter intervention in Europe and North America.28,29 The prognosis of AS is negatively affected by the presence of symptoms and aortic valve replacement (AVR) is indicated once symptoms occur.29,30 Although up to 50% of patients with severe AS claim to be asymptomatic at diagnosis, patients may unconsciously adapt their lifestyle by reducing their activity levels or attributing exercise intolerance to other reasons, such as ageing or noncardiac comorbidities.31,32 Hence, symptom status assessment in patients with severe AS is challenging. In addition, about 30% of patients with moderate AS have exercise intolerance and the role of AS in this exercise limitation needs careful examination.33 Furthermore, the assessment of AS severity relies on the evaluation of aortic valve area (AVA) and transvalvular pressure gradients. Currently, AS is considered severe when AVA is ≤ 1 cm2 and aortic jet velocity is >4 m/s or the mean transvalvular gradient is ≥40 mmHg.29,30 Although AVA is theoretically the ideal determinant of AS severity, AVA may be underestimated in low-flow states, such as in the presence of reduced ventricular systolic function (LVEF <50%) or in patients with preserved LVEF and low antegrade flow, such as small left ventricular cavity, marked

left ventricular hypertrophy or significant mitral regurgitation.34–37 Therefore, comprehensive assessment of AS severity is extremely relevant and there is growing interest on the use of provocative manoeuvres for this purpose. Currently, the 2017 European Society of Cardiology (ESC)/European Association for Cardiothoracic Surgery (EACTS) guidelines for the management of valvular heart disease recommend surgical aortic valve replacement (SAVR) for patients with severe AS in which symptoms are unmasked (Class I, level of evidence [LOE] C) or in those with a fall in blood pressure (Class IIa, LOE C) during exercise testing. SAVR is also recommended (Class IIa, LOE C) in patients with pulmonary hypertension (systolic pulmonary pressure >60 mmHg).29 However, the discrimination between AS-related symptoms versus deconditioning, frailty, or other causes of dyspnoea on exertion is problematic in a traditional exercise test and invasive documentation of haemodynamic derangement might be particularly helpful. In this scenario, Lancellotti et al. demonstrated in 105 patients with severe asymptomatic AS undergoing stress echocardiography that the development of exercise-reduced pulmonary hypertension observed in 55% of these cases is associated with a twofold increase in the incidence of adverse cardiac events. Exercise-induced pulmonary hypertension defined in this study as estimated pulmonary artery systolic pressure >60 mmHg during exercise was derived from regurgitant jet velocity of the tricuspid valve. Thirty-five cases were excluded because of the absence of measurable pulmonary artery systolic pressure during exercise, potentially preventing the use of non-invasive assessment of exercise-induced pulmonary hypertension in this patient population.38 Our laboratory and van Riel et al. have demonstrated development of flowrelated pressure gradients between the right ventricle and the pulmonary artery during exercise.39,40 As such, the assumption that calculated right ventricular systolic pressure (the sum of right atrial pressure and transtricuspid pressure gradient, derived from regurgitant jet velocity of tricuspid regurgitation) is an accurate surrogate of pulmonary artery systolic pressure during exercise may be flawed. Hence, in patients with non-diagnostic stress echocardiography, exercise right heart catheterisation may be considered.

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A Guide to Exercise Right Heart Catheterisation In a population of 33 patients with asymptomatic moderate or severe AS who underwent exercise right heart catheterisation, lower values of pulmonary artery oxygen saturation at peak exercise were associated with worse clinical outcomes at the 2-year follow-up period.41 Although this finding may point towards an association between poor outcomes and attenuation of CO increase during exercise in this population, the lack of CO measurements during exercise precludes definitive conclusion in this aspect and this hypothesis needs to be further addressed. In this setting, in a cohort of 39 patients with severe asymptomatic AS, Christensen et al. demonstrated a positive correlation between left atrium dilatation and both PAWP and MPAP at rest and during exercise. Notably, remarkably elevated PAWP during exercise was observed in 85% of these cases, despite normal PAWP at rest in about 50% of the population. Importantly, changes in MPAP and PAWP during exercise were associated with increased risk of a composite outcome of aortic valve replacement, unplanned hospitalisation or death.42 Accordingly, exercise right heart catheterisation might further refine the understanding of potential contributions of AS in the genesis of haemodynamic derangements by putting in perspective the behaviour of pulmonary vasculature and left-sided filling pressure responses in relation to flow responses. The prognostic implication of haemodynamic abnormalities disclosed during exercise in this population is still not fully explored and there is tremendous opportunity for future research in this field.

Mitral Valve Diseases Mitral Stenosis

Mitral stenosis is the only valvular heart lesion that is still mostly caused by rheumatic heart disease in developed countries and despite the fact that the prevalence of degenerative calcific mitral stenosis has increased as the population has aged, the natural history of the latter is not clearly understood and significant non-rheumatic mitral stenosis is rare.43,44 The prognostic and symptomatic burden of mitral stenosis is strongly related to the haemodynamic consequences of transmitral gradients and development of pulmonary hypertension.45 Resting measurements might underestimate the functional haemodynamic consequences of mitral stenosis and exercise testing is recommended when discrepancies between mitral stenosis severity and symptoms are encountered.29,30 In symptomatic patients with severe mitral valve stenosis, mitral valve interventions are recommended, preferably by percutaneous mitral valve commissurotomy.29,30 Furthermore, in order to reduce the negative consequences of mitral stenosis, percutaneous mitral commissurotomy is recommended in asymptomatic patients with pulmonary hypertension or with other features that might suggest higher risk of haemodynamic decompensation. Haemodynamic features of precapillary pulmonary hypertension do not correlate with left atrial pressure values at rest and the severity of mitral stenosis is not a reliable predictor of pulmonary pressures.46 In a study of 53 ambulatory patients with mitral stenosis, Reis et al. demonstrated that mean diastolic mitral valve gradient at peak dobutamine stress echocardiography ≥18 mmHg predicted cardiovascular hospitalisation and the incremental prognostic power of dobutamine stress echocardiography was most pronounced among patients with a mitral valve area between >1 cm2 and ≤1.5 cm2.47 However, this study included mostly symptomatic patients and thus the prognostic role of dobutamine stress echocardiography in asymptomatic patients with mitral stenosis remains unclear. In patients with discrepancies between

symptoms and mitral stenosis severity, resting indexes are not able to identify poor exercise capacity or the development of severe pulmonary hypertension at exercise.48 The use of combined exercise right heart catheterisation and Doppler echocardiography in the assessment of mitral stenosis was demonstrated more than two decades ago. Through assessment of transvalvular mitral valve flow, assessed by the thermodilution technique, divided by mean transmitral flow velocity, Voelker et al. challenged the dogma that stenotic mitral valve area would be fixed during exercise.49 Two subgroups were identified: those with mitral valve reserve defined by an increase in mitral valve area >20% and those without (<20% increase in mitral valve area at exercise). Despite similar mitral valve area at rest and similar change in mean transmitral flow velocity during exercise, patients with mitral valve reserve demonstrated greater increases in CO and transvalvular flow. Also, whereas exercise resulted in stroke volume augmentation among those with mitral valve reserve, stroke volume decreased during exercise in patients without mitral valve reserve. Therefore, CO augmentation was driven exclusively by increases in heart rate in those without mitral valve reserve. The exercise effective mitral valve area <1.2 cm2, calculated according to the method described above, had higher sensitivity and specificity to detect severe mitral stenosis than other haemodynamic measurements. In summary, in the setting of mitral stenosis, the correlation between resting indexes and decreased exercise capacity or severe haemodynamic derangements at rest or during exercise is poor. Although, exercise right heart catheterisation, preferably combined with Doppler echocardiography, might provide valuable incremental information on the haemodynamic repercussions of mitral stenosis, the clinical usefulness and prognostic implication of exercise haemodynamic findings remain to be determined.

Mitral Regurgitation

Mitral regurgitation (MR) is the most prevalent valvular disease in developed nations and it is the second most common cause for cardiac valve surgery in Europe.43,50 Whereas primary MR is related to derangements at the mitral valve apparatus level, secondary (also known as functional) MR is most frequently related to imbalance between closing and tethering forces on the mitral valve as a result of altered left ventricular geometry. Indications for intervention differ between primary and secondary MR and will be discussed separately.

Primary Mitral Regurgitation

In primary MR, symptoms usually occur first during exercise and the onset of symptoms represents a key landmark in the course of disease. Symptom onset may be insidious and decreased functional capacity might be unappreciated in chronic MR. The correlation between exercise haemodynamic derangements and the contribution of MR might be particularly informative in the setting of chronic MR. Currently, the ESC/EACTS guidelines encourage the use of exercise to determine functional capacity in asymptomatic patients with primary MR, with particular attention to significant increases in systolic pulmonary arterial pressure.29 Similarly, the American Heart Association/American College of Cardiology guidelines also support the use of exercise haemodynamic assessment when discrepancies between MR severity and symptoms are observed or when the degrees of LA and/or LV remodelling are apparently disproportionate to the degree of MR (Class IIa, LOE B).30

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A Guide to Exercise Right Heart Catheterisation Figure 3: Systolic Pulmonary Artery Pressure and Cardiac Output Relationship Pre- and Post-percutaneous Edge-to-edge Mitral Valve Repair p=0.039

SPAP (mmHg) 70

*p=0.030 p=0.17

60 p=0.033

95% CI Pre-clip

p=0.041

Post-clip 30

Percutaneous edge-to-edge mitral valve repair resulted in an improved exercise haemodynamic profile in a small study, reinforcing the pathophysiological relevance of treating secondary MR (Figure 3).58 Although the concept of using invasive haemodynamic assessment as a strategy to identify responders to mitral valve interventions in the setting of secondary MR might hold promise, data to support such a strategy is still scant and future research should address this hypothesis.

Tricuspid Regurgitation

*p=0.036 40

secondary MR is currently acknowledged as a potential target for optimal treatment of heart failure.57

Cardiac output (l/min)

* SPAP/CO. CO = cardiac output; SPAP = systolic pulmonary artery pressure. Source: Heyning et al. 2016.58 Used with permission from Elsevier.

In asymptomatic patients with chronic primary MR, remarkably elevated systolic pulmonary artery pressures (SPAP >60 mmHg), observed in 46% of patients in this study, were associated with worse prognosis in up to 2-year follow-up.51 Also, despite overall unremarkable haemodynamic findings at rest, SPAP >60 mmHg was observed in one-third of asymptomatic patients with chronic primary MR in a study that included symptomatic and asymptomatic patients with chronic primary MR. Peak oxygen consumption was not different between these two groups, reinforcing the potential relevance of comprehensive assessment of exercise haemodynamic parameters.52 Therefore, in the rapidly evolving field of surgical and percutaneous interventions for the management of primary MR, exercise right heart catheterisation might further refine the assessment of asymptomatic patients with underlying exercise-induced pulmonary hypertension and a worse prognosis and it might also be particularly helpful in clarifying discrepancies between MR severity and the presence of symptoms.

Secondary Mitral Regurgitation

Secondary MR most frequently reflects altered closing and tethering forces on the mitral valve as a result of altered LV geometry. Secondary MR has been strongly related to decreased quality of life, increased rate of hospitalisation for congestive heart failure and increased mortality.53,54 During exercise, increasing the degree of functional MR leads to attenuation of increase in forward stroke volume and increased backward flow results in a disproportionate increase in left atrial and pulmonary pressures, therefore increasing the pulsatile load in the pulmonary circulation.55 Worsening of MR during exercise has been associated with impaired exercise capacity, even when MR is modest at rest.56 The results of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial, in which transcatheter treatment of significant secondary MR was associated with a 47% risk reduction in the occurrence of hospitalisation for heart failure within 24 months follow-up, as well as significant mortality rate reduction and improved quality of life and functional capacity have changed the landscape in the field of secondary MR treatment; previously considered a marker of advanced heart failure,

Tricuspid regurgitation is most commonly caused by tricuspid valve annular dilatation and/or right ventricle enlargement and is also known as functional tricuspid regurgitation. It is associated with a worsened prognosis and decreased functional capacity, regardless of left-sided heart disease or pulmonary hypertension.59,60 Recent developments in the field of transcatheter tricuspid valve interventions have changed the landscape in the management of functional tricuspid regurgitation. However, there is a lack of understanding on the subgroups of patients that could benefit from transcatheter tricuspid valve interventions and most cases are performed on a compassionate basis.61 Functional tricuspid regurgitation is often associated with other cardiovascular diseases, such as AF, heart failure with both preserved and reduced ejection fraction, MR or pulmonary hypertension and these comorbid conditions may confound the assessment of tricuspid regurgitation’s contribution to the pathogenesis of decreased functional capacity in this scenario. In a study that included invasive haemodynamic assessment during exercise, mismatch between CO and metabolic needs have been demonstrated in the setting of severe functional tricuspid regurgitation. This study also demonstrated abnormal PAWP response to exercise in a population of patients with isolated tricuspid regurgitation and without left-sided heart disease, raising the possibility that pulmonary venous congestion might contribute to exercise intolerance in this patient population. Also, despite abnormally increased PAWP, LV transmural pressure substantially decreased during exercise, indicating reduced LV preload at exercise, potentially driven by the occurrence of right ventricular dilatation and consequent direct ventricular interaction during exercise.62 Exercise right heart catheterisation may present the opportunity to thoroughly assess right ventricular systolic function and right ventricular contractile reserve, which may be relevant for the selection of patients who might benefit from transcatheter tricuspid valve interventions, refining the indications for the use of this evolving technology.63,64 Alternatively, there are limited tools to identify patients who are less likely to benefit from transcatheter tricuspid valve interventions, as patients with pulmonary arterial hypertension and severe tricuspid regurgitation have poor survival rates.65 Thus, demonstration of remarkable pre-capillary exercise pulmonary hypertension haemodynamic phenotype might represent a subgroup of patients in whom tricuspid valve interventions may not be beneficial for the primary haemodynamic abnormality. However, there is lack of consensus on how to perform such assessments and data in this setting is still scarce, limiting the clinical applicability of exercise right heart catheterisation in this specific scenario.

Conclusion

Exercise right heart catheterisation may objectively unmask symptoms and underlying haemodynamic abnormalities that are not evident at

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A Guide to Exercise Right Heart Catheterisation rest. Furthermore, it may facilitate the distinction between pre- and post-capillary pulmonary hypertension. As the field of transcatheter interventions for valvular heart disease continues to grow, the potential 1.

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36. Hachicha Z, Dumesnil JG, Bogaty P, et al. Paradoxical low-flow, low-gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival. Circulation 2007;115:2856– 64. https://doi.org/10.1161/CIRCULATIONAHA.106.668681; PMID:17533183. 37. Clavel MA, Dumesnil JG, Capoulade R, et al. Outcome of patients with aortic stenosis, small valve area, and low-flow, low-gradient despite preserved left ventricular ejection fraction. J Am Coll Cardiol 2012;60:1259–67. https://doi. org/10.1016/j.jacc.2011.12.054; PMID: 22657269. 38. Lancellotti P, Magne J, Donal E, et al. Determinants and prognostic significance of exercise pulmonary hypertension in asymptomatic severe aortic stenosis. Circulation 2012;126:851–9. https://doi.org/10.1161/ CIRCULATIONAHA.111.088427; PMID: 22832784. 39. Wright SP, Opotowsky AR, Buchan TA, et al. Flow-related right ventricular to pulmonary arterial pressure gradients during exercise. Cardiovasc Res 2019;115:222–9. https://doi. org/10.1093/cvr/cvy138; PMID: 29878071. 40. van Riel ACMJ, Systrom DM, Oliveira RKF, et al. Development of a right ventricular outflow tract gradient during upright exercise: a hemodynamic observation. J Am Coll Cardiol 2017;69:595–7. https://doi.org/10.1016/j. jacc.2016.11.039; PMID: 28153114. 41. Dobarro D, Castrodeza-Calvo J, Varela-Falcón L, et al. Exercise right heart catheterization predicts outcome in asymptomatic degenerative aortic stenosis. Rev Esp Cardiol (Engl Ed) 2019;73:457–62. https://doi.org/10.1016/j. rec.2019.03.005; PMID: 31078458. 42. Christensen NL, Dahl JS, Carter-Storch R, et al. Association between left atrial dilatation and invasive hemodynamics at rest and during exercise in asymptomatic aortic stenosis. Circ Cardiovasc Imaging 2016;9:e005156. https://doi. org/10.1161/CIRCIMAGING.116.005156; PMID: 27894069. 43. Iung B, Vahanian A. Epidemiology of acquired valvular heart disease. Can J Cardiol 2014;30:962–70. https://doi. org/10.1016/j.cjca.2014.03.022; PMID: 24986049. 44. Abramowitz Y, Jilaihawi H, Chakravarty T, et al. Mitral annulus calcification. J Am Coll Cardiol 2015;66:1934–41. https://doi.org/10.1016/j.jacc.2015.08.872; PMID: 26493666. 45. Baumgartner H, Hung J, Bermejo J, et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr 2009;22:1–23. https://doi.org/10.1016/j.echo.2008.11.029; PMID: 19130998. 46. Otto CM, Davis KB, Reid CL, et al. Relation between pulmonary artery pressure and mitral stenosis severity in patients undergoing balloon mitral commissurotomy. Am J Cardiol 1993;71:874–8. https://doi.org/10.1016/00029149(93)90844-3; PMID: 8456774. 47. Reis G, Motta MS, Barbosa MM, et al. Dobutamine stress echocardiography for noninvasive assessment and risk stratification of patients with rheumatic mitral stenosis. J Am Coll Cardiol 2004;43:393–401. https://doi.org/10.1016/j. jacc.2003.09.037; PMID: 15013120. 48. Grimaldi A, Olivotto I, Figini F, et al. Dynamic assessment of ‘valvular reserve capacity’ in patients with rheumatic mitral stenosis. Eur Heart J Cardiovasc Imaging 2012;13:476–82. https://doi.org/10.1093/ejechocard/jer269; PMID: 22143399. 49. Voelker W, Karsch KR. Exercise Doppler echocardiography in conjunction with right heart catheterization for the assessment of mitral stenosis. Int J Sports Med 1996;17(Suppl 3):S191–5. https://doi.org/10.1055/s-2007-972923; PMID: 9119542. 50. Iung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24:1231–43. https://doi.org/10.1016/S0195668X(03)00201-X; PMID: 12831818. 51. Magne J, Lancellotti P, Piérard LA. Exercise pulmonary hypertension in asymptomatic degenerative mitral regurgitation. Circulation 2010;122:33–41. https://doi. org/10.1161/CIRCULATIONAHA.110.938241; PMID: 20566950. 52. Bakkestrøm R, Banke A, Christensen NL, et al. hemodynamic characteristics in significant symptomatic and asymptomatic primary mitral valve regurgitation at rest and during exercise. Circ Cardiovasc Imaging 2018;11:e007171. https://doi.org/10.1161/CIRCIMAGING.117.007171; PMID: 29449412. 53. Grigioni F, Enriquez-Sarano M, Zehr KJ, et al. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment.

A Guide to Exercise Right Heart Catheterisation

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Coronary

Balloon Pulmonary Angioplasty: State of the Art John G Coghlan ,1 Alexander MK Rothman2 and Stephen P Hoole3 1. Royal Free Hospital, London, UK; 2. Sheffield Teaching Hospitals NHS Trust, Sheffield, UK; 3. Royal Papworth Hospital, Cambridge, UK

Abstract

Balloon pulmonary angioplasty (BPA) is a novel technique for the treatment of chronic thromboembolic pulmonary hypertension. While cardiologists need no introduction to the concept of balloon angioplasty, BPA has its own particular challenges. This article aims to provide the reader with an overview of BPA, starting with an introduction to chronic thromboembolic disease (CTED), the standard management of chronic thromboembolic pulmonary hypertension (CTEPH), technical challenges faced when performing BPA and the evidence base supporting its use. The second part of the article will focus on the future of BPA, in particular the areas where research is required to establish an evidence base to justify the role of BPA in CTEPH and CTED treatment.

Keywords

Thromboembolic, thromboembolism, pulmonary, angioplasty, riociguat, endarterectomy, complications Disclosure: JC performs balloon pulmonary angioplasty at Royal Papworth Hospital. Unrelated to the current work he receives grants from Johnson & Johnson and Merck. He undertakes consultancy work and has received honoraria from Johnson & Johnson, GSK, Bayer and Endotronix. AR performs balloon pulmonary angioplasty at Royal Papworth Hospital. Unrelated to the current work he receives grants from Johnson & Johnson, Novartis, Medtronic and Abbott. He undertakes consultancy work and has received honoraria from Johnson & Johnson, SoniVie and Endotronix. SH performs balloon pulmonary angioplasty at Royal Papworth Hospital. Unrelated to the current work he has received research grants from AstraZeneca and Abbott Vascular. He undertakes consultancy work and has received honoraria from AstraZeneca, Bayer, Abbott Vascular and Boston Scientific. Received: 22 April 2020 Accepted: 1 September 2020 Citation: Interventional Cardiology Review 2020;16:e02. DOI: https://doi.org/10.15420/icr.2020.14 Correspondence: JG Coghlan, Royal Free Hospital, Pond St, London NW3 2QG, UK. E: gerry.coghlan@nhs.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Pathophysiology of Chronic Thromboembolic Pulmonary Hypertension and Chronic Thromboembolic Disease

Chronic thromboembolic disease (CTED) is believed to develop when acute pulmonary emboli (PE) fail to dissolve by autolysis after a 3-month period of anticoagulation. Residual defects can be identified in up to 50% of patients when studied using lung perfusion scintigraphy 3–12 months after an acute PE.1,2 The thromboembolic material is replaced by fibrotic material, develops an endothelial covering and cannot be cleared by anticoagulation or thrombolytic therapy.3 Despite the prevalence of residual intravascular material, the development of pulmonary hypertension is uncommon – reported to be <1% in clinical practice, and 2–3% in the prospectively followed Pulmonary Embolism Thrombolysis (PEITHO) study.4,5 Chronic thromboembolic pulmonary hypertension (CTEPH) is present when, in addition to CTED, pulmonary pressures are raised to abnormal levels and is usually associated with significant effort limitation. Since the 6th World Symposium on Pulmonary Hypertension (WSPH), this has been redefined as a mean pulmonary artery pressure (mPAP) of >20 mmHg with a pulmonary vascular resistance (PVR) of ≥3WU.6 However, prior to 2019 the convention was to diagnose pulmonary hypertension only where the mPAP was ≥25 mmHg – thus all studies published to this date relied on the previous definition. This is an important distinction to acknowledge when applying trial data to clinical practice.

Pulmonary hypertension in CTEPH does not necessarily correlate with the volume of obstructive material, but is augmented by an additional vasculopathy that develops months to years after the initial event.3,4 Among those who develop CTEPH, pulmonary hypertension usually fails to resolve after an acute PE with breathlessness persisting and worsening over time as the associated vasculopathy progresses. In 23% of cases there is no obvious acute preceding event.7 Whether this implies a subclinical initial event followed by progressive vasculopathy is not yet established.

Management Options in Chronic Thromboembolic Pulmonary Hypertension

The established intervention for managing CTEPH is surgical pulmonary endarterectomy (PEA).4 This is technically feasible in 60% of patients with CTEPH and is associated with excellent symptomatic, haemodynamic and prognostic outcomes.7 In-hospital mortality has been reported at around 5% in the international CTEPH registry, although the largest centres currently report a 30-day mortality of 2.2%.7,8 Three-year survival has been reported at 89% in operated patients versus 70% in unoperated patients.7 In patients deemed surgically operable but who declined intervention, only 55% survived to 5 years compared to 83% who underwent PEA.9 In patients with inoperable or post-PEA CTEPH, medical therapy with riociguat has been shown to improve 6-minute walk distance and modestly reduce mPAP (<10%) and is the only licensed therapy for this condition.10

Balloon Pulmonary Angioplasty Table 1: Overview of Studies Demonstrating Haemodynamic Response to Balloon Pulmonary Angioplasty Author

Centre

Start Date

End Date

Age

In-hospital/ 30-day Mortality

Pre-BPA Post-BPA Pre-BPA Post-BPA mPAP mPAP PVR PVR

Pre-BPA PostCardiac BPA Index Cardiac Index

Feinstein et al. 200112

Boston

Oct 04

Jan 09

52.7

5.6%

42 ± 12

34 ± 10

2.0 ± 0.4

2.1 ± 0.6

Osaka

Jun 11

Oct 15

42 ± 11

26 ± 6

11 ± 5.3

5.1 ± 2.3

2.3 ± 0.6

2.6 ± 0.6

Tatabe et al. 2016

Tohoku

Mar 12

Dec 14

35*

35 ± 9

24 ± 6

6 ± 2.8

3.2 ± 1

2.6 ± 0.6

2.7 ± 0.6

Broch et al. 201624

Oslo

2003

2014

44 ± 11

33 ± 9

7.7 ± 3.5

4.7 ± 2.8

Ogawa et al. 2017

Japan × 7

Nov 04

Mar 13

380

2.6%

43 ± 11

24 ± 6

10.7 ± 5.6

4.5 ± 2.8

2.6 ± 0.7

2.9 ± 0.6

Yokoawa et al. 201726

Fukushima

Sep 12

Mar 18

22*

13.6%

45 ± 8

28 ± 7

2.4 ± 0.8

2.8 ± 0.8

Nagao et al. 201727

Kyushu

May 12

Dec 15

Kreichbaum et al. 201828

Bad Nauheim

Mar 14

Mar 17

39.5 ± 12

32.6 ± 13

6.5 ± 2.7

5 ± 2.5

2.5 ± 0.6

2.5 ± 0.5

Velazquez et al. 201929

Madrid

May 13

Feb 17

2.1%

49.5 ± 12

38 ± 9

10.1 ± 4.9

5.6 ± 2.2

2.3 ± 0.5

2.7 ± 0.5

Brenot et al. 201930

Paris

2014

2017

184

2.2%

44 ± 9.5

32 ± 9

7.5 ± 2.8

4.1 ± 2.2

2.7 ± 0.6

3.1 ± 0.8

Siennicka et al. 201931

EHC

Dec 15

Sep 18

1.7%

49 ± 11

9.5 ± 4.3

2.3 ± 0.7

Maschke et al. 201932

Hannover

Aug 13

Jan 17

42 ± 11.5

35 ± 12

Kimura et al. 201933

Keio

Nov 12

Sep 17

123

6.8

3.4

Ikeda et al. 201934

Toho

May 14

Apr 17

35 ± 10

22 ± 6

6.2 ± 3.1

2.9 ± 1.1

2.7 ± 0.8

2.9 ± 0.8

Godinas et al. 201935

Leuven

July 14

July 18

44 ± 12

31 ± 12

8.4 ± 3.6

4.6 ± 3.3

2.3 ± 0.4

2.7 ± 0.6

Hoole et al. 202018

Papworth

Oct 15

Sep 18

45 ± 11

34 ± 8

8.3 ± 3.5

5.5 ± 2.5

van Thor et al. 202036

The Netherlands

Jun 15

Feb 19

40 ± 12

313 ± 8

6.1 ± 4.7

3.3 ± 2

2.9 ± 1.1

3.0 ± 0.8

Ogo et al. 201622 23

*For Tatabe et al., details on 35 of 55 patients studied provided and for Yokoawa et al. only details on 19 survivors reported. This table has been constructed from 42 studies. Where significant overlap between enrolment periods in the same institutions existed, the study with the larger number of patients has been selected. Some patients may therefore be missing or there may be some double counting. Marginal overlap has been accepted. BPA = balloon pulmonary angioplasty; EHC = European Health Centre; mPAP = mean pulmonary artery pressure; NR = not reported; PVR = pulmonary vascular resistance.

Long-term data suggesting prognostic benefit are based on open-label follow-up in the BAY63-2521 – Long-term Extension Study in Patients With Chronic Thromboembolic Pulmonary Hypertension (CHEST-2) trial with an estimated 93% 2-year survival rate among the 62% of the study population who continued therapy for at least 2 years.11 Unlicensed medical therapy (phosphodiesterase inhibitors and endothelin receptor antagonists) was not associated with improved survival in the international CTEPH registry.7

disease (n=16) or being unfit for surgery (n=2).12 Patients underwent an average of 2.7 BPA sessions, targeting an average of six lesions per patient. Mean PAP fell by 9 mmHg without a change in cardiac index, symptoms (New York Heart Association score improved by 1.5) and walk distance improved by 288 m. However, adverse events were common. One patient died 7 days post procedure and 11 developed reperfusion oedema, three requiring mechanical ventilation.

The first series of balloon pulmonary angioplasty (BPA) was reported nearly 20 years ago by Feinstein et al.12 The technique has subsequently been refined in multiple centres in Japan and is now rapidly being adopted in Europe and the US.13–19

In Europe and the US, the high complication rate associated with BPA led to a focus on refining PEA and developing medical therapies for CTEPH. However in Japan, work on refining BPA continued. A decade later, a number of publications from several centres demonstrated that BPA performed in a staged fashion reduced the risk of lung injury, was associated with significant haemodynamic and symptomatic benefit and appeared to improve survival.13 By 2013, as progress with medical interventions was proving slow and approximately one-third of patients were still deemed to have surgical inaccessible disease, major European centres began to perform BPA. Table 1 outlines the registries published to date (excluding, where possible, those covering the same population more than once).22–36

Balloon Pulmonary Angioplasty Development

The first report of BPA for CTEPH was by Voorburg et al. in 1988, who dilated four lesions in a 30-year-old patient, reducing mPAP by 24% (from 46 to 35 mmHg).20 Parallel work in animal models and patients with congenital stenoses provided insights into the required degree of stenosis dilation and maximum tolerated balloon diameter to vessel ratio.21 Given this background, improvements in angioplasty equipment and the poor outcomes in patients who were not candidates for PEA surgery, Feinstein et al. performed BPA in 18 patients deemed either to have non-surgical

Imaging Modalities

Selective pulmonary angiography is an essential as part of the BPA procedure. However, selecting patients and target territories requires

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Balloon Pulmonary Angioplasty familiarity with several other modalities. Most centres use a multimodal assessment, including lung scintigraphy, CT pulmonary angiography and high-quality invasive pulmonary angiography, to identify targets, with the latter providing information on the dynamic flow through target lesions, localised parenchymal perfusion and venous return.19,30 While useful for proximal disease, MR pulmonary angiography currently has a limited role in imaging the segmental and often subsegmental disease targeted in BPA, although cardiac MR to document the right ventricle (RV) state before and in response to BPA is clearly of value.37

Figure 1: Multiple Lesion Types on Pulmonary Angiogram

Dual energy CT scanning has the potential to combine the strengths of scintigraphy and CT scanning, providing anatomical and perfusion imaging with a single investigation.38 However, this is an expensive modality with limited general applicability, and so single energy subtraction CT is being explored because it offers similar information without the need for dedicated equipment.39 C-arm CT 3D subtracted imaging (cone beam CT) of the pulmonary arteries has also been reported.22,32 The superior soft tissue imaging allows tracing of the course of occluded vessels and blending with fluoroscopic images allows tracing of the direction for guidewire advancement in three dimensions. In addition, superior resolution allows detail of the lesions to be resolved prior to intervention (webs, slits, subtotal and total occlusions) and allows accurate planning of required balloon size. While laborious, this has been associated with very low complication rates (no complications in 89% of 266 sessions and only 1.5% experiencing complications that required active management).32 Similar information is available non-invasively with a more readily available technique of ECG gated 320-row area detector CT scanning.22 Intravascular ultrasound (IVUS) has been used to accurately size vessels to be treated thus avoiding over-inflation and vascular damage, with virtual histology being explored to identify lesions most likely to respond to balloon dilation.40,41 Optical coherence tomography (OCT) provides unparalleled detail of the lesions being treated but at the cost of substantially greater contrast administration.42 From OCT studies we have learned that the standard ambition of dilating lesions to 0.8 of the reference vessel size is not currently achievable in most (70%) of lesions because of the complex nature of the lesions being treated (thick multihole webs) or elastic recoil (thick walled mono-hole).42

A: Pouch occlusion (partial filling of distal vessel seen to fill in this instance creating a potential target for wire access; B: tapered occlusive disease; C: Stenotic lesion; D: Tapered occlusion; E: Complex web disease; F: Web disease, with slit lesion. Note parenchymal perfusion is evident around the upper lobe vessels, much less so in the middle and lower lobes in this patient.

Figure 2: Occlusive Web Disease

Procedural Details

BPA is carried out via either the femoral or jugular route and guiding catheters passed to the pulmonary arteries. Buffeting of the catheter by the right ventricle and movement of the pulmonary vasculature with respiration is minimised by the use of a long (65–80 cm) sheath and instrumenting target vessels during breath-hold.18,34 Most operators have found that hydrophilic guidewires facilitate crossing of complex webs, but these need careful handling to minimise the most common complication – wire perforation (Table 1). Target vessels are segmental and subsegmental vessels, although lobar vessels (more usually a target for PEA) have been treated.22 The most common balloon sizes are 2–4 mm, although larger sizes (up to 14 mm) have been reported.16–18,34,43,44 The aim is to restore normal flow with rapid filling of the draining pulmonary veins, although pressure wire and microcatheters have been used to achieve a distal pressure of 0.75–0.8 of proximal pressure where mPAP is <35 mmHg.43,44 Targets for treatment depend on lesion characteristics (webs, stenoses and tapered occlusions/subtotal occlusions in preference to abrupt occlusions; Figures 1–3) in areas of reduced parenchymal perfusion.19 The success rate is highest (99%) and complication rate lowest (2%) for ring

A: Occlusive web disease before (arrow) balloon dilation. B: Occlusive web disease after balloon dilation. Ring stenosis is clearly seen (arrow).

and web lesions, while the success rate is lowest for total occlusions (52%) and the complication rate highest in tortuous vessels (43%).45 In territories where perfusion is reduced but no lesion is visible at angiography, one may still encounter webs that require dilatation; thus perfusion defects are regarded as more important than angiographically visible lesions in choosing segments to interrogate.19 Because of the greater physiological impact, lower lobe vessels are prioritised and the right lung over the left lung. Guidewire support using a balloon or

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Balloon Pulmonary Angioplasty Figure 3: Complex Web Disease

FC is also consistently improved, with the vast majority of patients achieving FC I/II after BPA. The 6MWD improved by 50–100 m in almost all studies (Table 2). Most studies have included measurement of brain natriuretic peptides and all have reported substantial reductions in these markers of myocyte stretch. As expected from PEA data, improvement but not normalisation of right ventricular function post BPA is consistently documented.18,24,53,54

Complex web disease before (A; arrow) and after (B) balloon dilation.

microcatheter is not unusual, but more aggressive techniques such as wire escalation is avoided where possible as the risk of wire exit increases significantly.18 Standard semi-compliant balloons are used for most procedures and cutting balloons are generally avoided – again to reduce complications in these thin-walled mobile vessels.19 Most patients require multiple BPA sessions (three to five being typical) and the interval between sessions varies from 3 days to 1 month or more (Table 2).18,19,46,47 Individual procedures are limited by the volume of lung treated (usually one or two lobes, although more extensive has been described), radiation dose (<2 Gy) and contrast volume (<4–6 ml/kg).19 Stenting is unnecessary as lesion recoil/recurrence is rare (three of 1,897 lesions restudied after >1 year had occluded).25 The exception is covered stents for major vascular injury.

Efficacy

A supportive evidence base is emerging for efficacy, including a metaanalysis suggesting superiority of BPA when compared to riociguat.48 The recently completed randomised controlled Riociguat Versus Balloon Pulmonary Angioplasty in Non-operable Chronic Thrombombolic Pulmonary Hypertension (RACE) trial (ERS 2019 abstract), included 124 patients randomised 1:1 to either BPA or riociguat. After 6 months PVR fell by 60% in the BPA group and 32% in the medical therapy group (p<0.001).49 The secondary endpoints change in mPAP, mean right atrial pressure, N-terminal pro-brain natriuretic peptide (NT-proBNP) and functional class (FC) showed greater improvement in the BPA group, although 6-minute walking distance (6MWD) was not significantly different between the two groups. Unsurprisingly, adverse events were significantly more common following BPA (50% versus 26%), although severe adverse events were less common (14% versus 9%) with haemoptysis and lung injury dominating in the BPA group and gastrointestinal adverse effects in the riociguat group. However, given their different sites of action, medical therapy and BPA are regarded as complementary.50 Registry data also support the role for BPA confirming a substantial reduction in mPAP, PVR and increase in cardiac index in patients undergoing BPA (Table 1). The haemodynamic effects are not seen during the procedure, but rather documented at follow-up at 52 ± 81 days.51 The actual timing of the benefit is unclear; however, among the 14 patients studied by Hosowaka et al, five were restudied within 1 month and pressures were already reduced.51 In another study, no further reductions were evident between 1 week after the final procedure and follow-up 2 years later.52

Although the evidence for mortality benefit is weak to date, there is some available. Siennicka et al. reported 58 patients undergoing BPA compared to 67 treated with medical therapy.31 Survival was superior in the BPA population at 92% (95% CI [85–99%]) versus 79% (95% CI [69–90%]) in those randomised to medical therapy during 22 months of follow-up. In addition, Tanigushi et al. reported improved survival in the French cohort since the introduction of BPA and with current practice BPA, but not medical therapy, was an independent predictor of survival (HR 0.297; CI 95% [0.098–0.907]).55 The BPA treatment effect appears to be durable. Inami et al. reported that among 30 of 57 eligible patients who underwent follow-up catheterisation after 50.3 months (interquartile range 47.4–55.6 months), mPAP and PVR remained >50% lower than baseline values.56 Ogawa et al. identified 196 patients who had undergone follow-up catheterisation at 425 ± 281 days after the last procedure.25 The authors reported near normal pressures and low rates of medical therapy usage (mPAP 22.5 ± 5.4 mmHg; PVR 288 ± 195 d.s.cm−5, 45% on medical therapy compared to 70% prior to BPA).

Safety

At the recent WSPH complications of BPA have been classified as shown in Table 3.6 Lung injury is the main issue; while this was previously thought to be due to reperfusion oedema, more recent data suggest that vascular trauma is the more likely explanation. Table 4 summarises the studies reporting adverse events in sufficient detail. In general, minor complications occur in 10–15% of sessions, but the largest study reported adverse events in 36%.25 The long-term significance of minor adverse events is yet to be determined although serious adverse events appear to be uncommon (Figures 4 and 5). Higher rates of lung complications are reported when using routine chest CT scanning after every procedure. Ikeda et al. reported on 30 patients whp underwent BPA to 879 lesions in 112 BPA sessions.34 Pulmonary artery perforations were identified in 21 lesions at angiography, but 93 hyperdense lesions (compatible with parenchymal haemorrhage) were observed at CT performed within 15 minutes of completion of BPA. Analysing by lesion showed that around 10% of web, ring and abrupt narrowing were associated with haemorrhage, while nearly 40% of occlusive lesions treated were associated with haemorrhage. Ejiri et al. confirmed these findings in a further CT study of 76 patients undergoing BPA to 1,247 vessels.57 In this study, vessel injuries identified at angiography were the strongest predictor of lung injury identified on CT scanning performed within 24 hours of the procedure (33% versus 2.5%). Of note, there is a clear learning curve, with experienced centres observing a significant reduction in adverse event rates in more recently treated patients (complication rates falling from 11.2% in the first 1,006 sessions to 7.7% in the most recent 562 sessions).30 Newer centres are learning to avoid the initial high complication rates, with Godinas et al. reporting a 10% complication rate in the first 90 procedures, only one of which was severe.35 Peri-procedural

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Balloon Pulmonary Angioplasty Table 2: Overview of Studies Reporting Clinical and Biomarker Response to Balloon Pulmonary Angioplasty Author

Sessions/ Women Patient (%)

Follow-up (months)

Pre-BPA Post-BPA Pre-BPA FC I/II (%) FC I/II (%) 6MWD (m)*

Post-BPA 6MWD (m)*

Pre-BPA NT-proBNP/ BNP (ng/l)*

Post-BPA NT-proBNP/ BNP (ng/l)*

Feinstein et al. 200112

2.7

209

497

Inami et al. 201443

103

3.4

360 (280–430)

420 (350–510)

95 (42–270)

34 (16–59)

Kinutani et al. 201644

303.0 ± 92

395 ± 124

160 ± 233

26.1 ± 30.5

Tatabe et al. 201623 35

3.5

100

408 ± 181

482 ± 146

252 ± 237

34 ± 23

Ogo et al. 2016

4.8

372 ± 124

470 ± 99

227 ± 282

48 ± 57

Aoki et al. 201746

380 ± 138

486 ± 112

55.8 (25–219)

25 (16–50)

Olsson et al. 2017

358 ± 108

391 ± 108

504 (233–1,676)

242 (109–555)

Yamasaki et al. 201747

2.7

396 ± 120

441 ± 104

Ogawa et al. 201725 380

4.6

318 ± 122

401 ± 105

240 ± 334

43 ± 76

Kreichbaum et al. 201828

375 (281–446)

821 (153–1872)

257 (115–508)

Brenot et al. 201930 184

5.5

396 ± 120

441 ± 104

Hoole et al. 202018

366 ± 107

440 ± 104

442 (168–1,607)

202 (155–447)

Velazquez et al. 201929

3.4

395 ± 112

468 ± 103

1,233 ± 1,327

255 ± 318

Siennicka et al. 201931

4.4

342 ± 142

3,005 ± 4,650

van Thor et al. 202036

4.5

374 ± 124

422 ± 125

195 (96–1,812)

154 (71–387)

*Data are presented as mean ± SD or median (IQR). 6MWD = 6-minute walking distance; BPA= balloon pulmonary angioplasty; FC = functional class; NT-proBNP = N-terminal pro-brain natriuretic peptide; NR = not reported.

mortality is generally reported to be approximately 2% per patient and is similar to PEA surgery in the best centres.58

Outstanding Issues

Several remaining issues need to be resolved to improve the efficacy and safety of BPA.

Pathophysiology of Chronic Thromboembolic Pulmonary Hypertension

From limited intravascular imaging and histology, we have a general sense of the nature of the lesions being treated and the mechanism of benefit.42,59 The lesions being addressed are largely fibrotic webs and stenosis, and much of the increase in cross sectional area is achieved through expansion of the vessel rather than compression of the intraluminal material.42,57,60,61 In a proportion, haemodynamics fail to improve despite clearing all the proximal disease.62 Whether this is due to persistent microvascular disease or distal unseen lesions that might be a target for intervention is, as yet, unresolved.63 The precise mechanism of benefit requires further evaluation. There is no immediate effect on pulmonary pressures – that appears later.51,52 Yet simultaneous haemodynamic and IVUS interrogation shows that pulmonary artery compliance increases immediately with no impact on distensibility or compliance at the site of treatment.59 In addition, further enlargement of the vessel tends to occur in the weeks to months post BPA, presumably induced by flow-mediated dilatation.44 More detailed understanding of this process will clearly be important going forward, to enable titration of treatment to effect in real time.

Table 3: World Symposium on Pulmonary Hypertension Classification of Complications of Balloon Pulmonary Angioplasty During the procedure Vascular injury* with/without haemoptysis Wire perforation Balloon overdilatation High-pressure contrast injection Vascular dissection Allergic reaction to contrast Adverse reaction to conscious sedation/local anaesthesia After the procedure Lung injury† (radiographic opacity with/without haemoptysis, with/without hypoxaemia) Renal dysfunction Access site problems *Signs of vascular injury: extravasation of contrast, hypoxaemia, cough, tachycardia, increased pulmonary arterial pressure. †Causes of lung injury: vascular injury much greater than reperfusion lung injury. Source: Jin et al. 2020.72 Reproduced from Baishideng Publishing Group under a Creative Commons (CC BY-NC-ND 4.0) licence.

Advances in Imaging Supporting Balloon Pulmonary Angioplasty

As mentioned above, several novel imaging techniques have the potential to improve outcomes in BPA. Subtraction CT by imaging diseased vessels supplying co-localised hypoperfused areas, could

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Balloon Pulmonary Angioplasty Table 4: Overview of Studies Reporting Details of Complications Associated with Balloon Pulmonary Angioplasty Author and Year

Sessions

Mortality

AE Rate

Wire Injury

PA Dissection or Perforation

Embolisation or Stent

Reperfusion or Lung Haemorrhage

Other

Feinstein et al. 200112

5.6%

47%

23%

Femoral pseudoaneurysm × 3

Ogo et al. 201622

385

16%

7.5%

0.3%

1.5%

4.7%

Haemoptysis 4.7%, Contrast allergy × 8

Ogawa et al. 201725

380

1,408

2.6%

36.3%

3.4%

1.3%

17.8%

Haemoptysis 14%, intubation × 17, ECMO × 9

Velazquez et al. 201929

156

2.1%

28%

2.4%

6.4%

0.6%

5.8%

Haemoptysis 12.8%, intubation + ECMO × 1

Brenot et al. 201930

184

1,006

2.2%

11.2%

3.7%

0.6%

9.1%

Haemoptysis 7.1%, NIV 3%, intubation with/ without ECMO × 4

Hoole et al. 202018 30

10.5%

3.2%

Haemoptyisis 5%, femoral pseudoaneurysm × 2

Maschke et al. 201932

266

10.9%

1.1%

2.2%

Haemoptysis 3%, dry cough 4.1%, atrial tachycardia × 1

Godinas et al. 201935

12%

Arrhythmia × 2, stress cardiomyopathy × 1

van Thor et al. 202036

172

12%

1.5%

Conduction disturbance/ arrhythmia 1.5%

AE = adverse event; ECMO = extracorporeal membrane oxygenation; NIV non-invasive ventilation; NR = not reported; PA = pulmonary artery.

Figure 4: Wire Exit

The Optimal Interventional Approach

To achieve optimal results safely, two main approaches are currently practiced. Addressing all accessible segments in each lung initially using a small balloon (2 mm), returning to that lung after a week or more with optimally sized balloons.22 The downside of this strategy is wiring large numbers of vessels at each session – wire trauma is thought to be the most common cause of lung injury.34,55 The alternate approach is limiting treatment the number of segments treated until the mean PAP is below 35 mmHg when a more aggressive approach is tolerated. We need to determine which of these approaches is optimal.18

Local haemorrhage from wire exit (A; arrow) and post coil implantation (B; arrow).

facilitate differentiation between disease amenable to intervention and microvascular disease. ECG gated area CT or cone beamed CT may identify treatable disease inadequately resolved on pulmonary angiography. Developments in MR perfusion mapping may create a role for MR in selecting territories to target and in monitoring changes in lung perfusion in response to BPA, reducing total radiation dose associated with repeated scintigraphy or CT scanning. Further work is necessary to define which of these techniques add value and should be incorporated into routine clinical usage. Virtual histology on IVUS or OCT add considerable complexity to the BPA procedure, but may provide insights into the optimal lesions to target, such information combined with improved non-invasive imaging may help further refine target lesion selection.

Dedicated equipment for BPA has not been a focus to date. Our industry partners are unlikely to invest resources unless the numbers of procedures performed increase significantly. Guide catheters, guide wires, intravascular imaging devices, etc., have all been borrowed from the coronary field and are not optimised for use in the larger, more mobile and thin-walled pulmonary vasculature. Given the data that complications are more severe among patients with very high pulmonary pressures, there is a logic to optimising medical therapy prior to BPA.42 Studies are required to determine whether optimising haemodynamics before BPA reduces the risks of the procedure.64

Novel Populations: Who Should be Offered Balloon Pulmonary Angioplasty?

The evidence base at present supports PEA surgery for proximal disease. However, registry data from Japan are beginning to suggest that BPA may eventually be in a position to challenge this orthodoxy (Table 1). A large international registry currently underway (NCT02656238) should provide evidence to allow planning of a BPA versus PEA trial in the next few years. The granularity of data in this registry will hopefully provide insights as to

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Balloon Pulmonary Angioplasty whether there are subgroups (such as those with dominantly occlusive disease) that should not be randomised and whether equivalent haemodynamic and symptomatic outcomes can be achieved.

Figure 5: CT Showing Pulmonary Haemorrhage

A second possible role of BPA is to lower the risk of intervention in patients where there are very adverse haemodynamic profiles or co-morbidities that render surgical risks unacceptable.65,66 If we can determine from the registry that in very high-risk patients BPA is associated with lower risks than PEA and that BPA does not disrupt the dissection plane for the surgeon, then BPA may well facilitate lower risk PEA in those with adverse haemodynamics. In the frail population we will need to confirm that BPA still confers net benefit.67 It is evident from published registries that BPA is both safe and effective in at least a proportion of the post-PEA population.25,31 However, this may depend on either inadequate initial clearance or recurrent disease. Where distal vasculopathy is the dominant driver for residual pulmonary hypertension, medical therapy may be the only effective option.56 In addition, not all lesions are surgically accessible in any individual patient so a hybrid approach with the surgeon focusing on proximal lesions and BPA to clear distal disease has been reported.68 Further work is required to fully characterise the population undergoing PEA and to understand where the risk benefit ratio favours a role for BPA either as part of a hybrid approach or for residual pulmonary hypertension post PEA. Because of the low risk of complications associated with BPA, particularly in patients with near normal haemodynamics, some centres have performed BPA on patients with CTED without pulmonary hypertension.69,70 Proving that the risk–benefit ratio is favourable in this population is fraught with difficulty – only with a sham control group can superiority be established, given the substantial placebo effect of intervention.71

Agreeing the Goals of Treatment

The ultimate goal of any intervention must be to improve symptoms, effort tolerance and prognosis. The goals must be tailored to the individual. Elderly patients may be satisfied with modest improvements in effort tolerance, in young patients normalisation of prognosis and exercise capacity are important objectives, while in patients with co-morbidities there will be limits to that which can be achieved by addressing the pulmonary vasculature and a different risk benefit balance. The procedural objectives, which are surrogates for these objectives, have yet to be validated. The initial approach was simply to tackle all accessible lesions if the mPAP remained >30mmHg.9 Variations are now emerging with some recommending a limited approach of predominantly targeting lower lobe vasculature (where the benefit is maximal and the risk lower).18 Most Japanese centres set a haemodynamic endpoint – typically an mPAP of <25 or even lower.22,25 Mahmud et al. suggest targeting improved 1.

D’Agostino C, Zonzin P, Enea I, et al. ANMCO Position paper: long-term follow-up of patients with pulmonary thromboembolism. Eur Heart J 2017;19(Suppl D):D309–32. https://doi.org/10.1093/eurheartj/sux030; PMID: 28751848. 2. Stevens H, Fang W, Clements W, et al. Risk stratification of acute pulmonary embolism and determining the effect on chronic cardiopulmonary complications: the REACH Study. TH Open 2020;4:e45–50. https://doi. org/10.1055/s-0040-1708558; PMID: 32259012. 3. Lang IM, Dorfmüller P, Vonk Noordegraaf A. The pathobiology of chronic thromboembolic pulmonary hypertension. Ann Am Thorac Soc 2016;13(Suppl 3):S215–21. https://doi.org/10.1513/AnnalsATS.201509-620AS; PMID: 27571003. 4. Kim NH, Delcroix M, Jais X, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2019;53:1801915.

perfusion on scintigraphy.19 Which of these approaches will yield the optimal risk–benefit ratio remains to be determined. Another possible approach would be to target right ventricular recovery, since it is right ventricular failure that determines prognosis. Whether through simple assessments of RV size and systolic function or more logically aiming to normalise RV-PA coupling or energetics, remains unclear.18,24,27 Initial studies from Japan have reported excellent haemodynamic outcomes while reducing adjuvant drug usage, following the example set in PEA surgery.25,58 Yet it is clear that CTEPH is a complex disease process where patients have a vasculopathy as well as obstructive disease.3 It is reasonable to suggest that on-going medical therapy may have a role post BPA to ensure optimal durability of the clinical benefit, but this has yet to be investigated in controlled studies.

Conclusion

BPA is now an established treatment modality for patients with inoperable CTEPH that – like coronary angioplasty – is destined to become part of standard therapy for this condition. We need to learn from the experience in coronary angioplasty and ensure that we do not allow BPA practice to expand without an adequate evidence base. Adequately powered randomised controlled trials and strong guideline-based limitations on practice are essential to achieve the best BPA results and improve outcomes of patients with CTEPH.

https://doi.org/10.1183/13993003.01915-2018; PMID: 30545969. 5. Konstantinides SV, Vicaut E, Danays T, et al. Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism. J Am Coll Cardiol 2017;69:1536–44. https://doi.org/10.1016/j.jacc.2016.12.039; PMID: 28335835. 6. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;53:1801913. https://doi.org/10.1183/13993003.019132018; PMID: 30545968. 7. Delcroix M, Lang I, Pepke-Zaba J, et al. Long-term outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. Circulation 2016;133:859–71.

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https://doi.org/10.1161/CIRCULATIONAHA.115.016522; PMID: 26826181. 8. Madani MM, Auger WR, Pretorius V, et al. Pulmonary endarter-ectomy: recent changes in a single institution’s experience of more than 2,700 patients. Ann Thorac Surg 2012;94:97–103. https://doi.org/10.1016/j. athoracsur.2012.04.004; PMID: 22626752. 9. Quadery SR, Swift AJ, Billings CG, et al. The impact of patient choice on survival in chronic thromboembolic pulmonary hypertension. Eur Respir J 2018;52:1800589. https://doi.org/10.1183/13993003.00589-2018; PMID: 30002102. 10. Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369:319–29. https://doi. org/10.1056/NEJMoa1209657; PMID: 23883377.

Balloon Pulmonary Angioplasty 11. Simonneau G, D’Armini AM, Ghofrani HA, et al. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med 2016;4:372–80. https://doi. org/10.1016/S2213-2600(16)30022-4; PMID: 27067478. 12. Feinstein JA, Goldhaber SZ, Lock JE, et al. Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Circulation 2001;103:10–13. https://doi.org/10.1161/01.CIR.103.1.10; PMID: 11136677. 13. Khan M, Amin E, Memon M, et al. Meta-analysis of use of balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension. Int J Cardiol 2019;291:134–9. https://doi.org/10.1016/j. ijcard.2019.02.051; PMID: 30850238. 14. Andreassen AK, Ragnarsson A, Gude E, et al. Balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension. Heart 2013;99:1415–20. https://doi.org/10.1136/ heartjnl-2012-303549; PMID: 23846611. 15. Bouvaist H, Thony F, Jondot M, et al. Balloon pulmonary angioplasty in a patient with chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2014;23:393–5. https://doi.org/10.1183/09059180.00000514; PMID: 25176976. 16. Roik M, Wretowski D, Rowinski O, et al. Refined balloon pulmonary angioplasty in inoperable chronic thromboembolic pulmonary hypertension – a multi-modality approach to the treated lesion. Int J Cardiol 2014;177:e139– 41. https://doi.org/10.1016/j.ijcard.2014.09.051; PMID: 25300656. 17. Olsson KM, Wiedenroth CB, Kamp JC, et al. Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension: the initial German experience. Eur Respir J 2017;49:1602409. https://doi. org/10.1183/13993003.02409-2016; PMID: 28596435. 18. Hoole S, Coghlan J, Cannon J, et al. Balloon pulmonary angioplasty for chronic thromboembolic disease – the UK experience. Open Heart 2020;7:e001144. https://doi. org/10.1136/openhrt-2019-001144; PMID: 32180986. 19. Mahmud E, Madani M, Kim N, et al. Chronic thromboembolic pulmonary hypertension: evolving therapeutic approaches for operable and inoperable disease. J Am Coll Cardiol 2018:71:2468–86. https://doi.org/10.1016/j.jacc.2018.04.009; PMID: 29793636. 20. Voorburg JA, Cats VM, Buis B, et al. Balloon angioplasty in the treatment of pulmonary hypertension caused by pulmonary embolism. Chest 1988;94:1249–53. https://doi. org/10.1378/chest.94.6.1249; PMID: 2973404. 21. Kreutzer J, Landzberg MJ, Preminger TJ, et al. Isolated peripheral pulmonary artery stenoses in the adult. Circulation 1996;93:1417–23. https://doi.org/10.1161/01.CIR.93.7.1417; PMID: 8641032. 22. Ogo T, Fukuda T, Tsuji A, et al. Efficacy and safety of balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension guided by cone-beam computed tomography and electrocardiogram-gated area detector computed tomography. Eur J Radiol 2017;89:270–6. https:// doi.org/10.1016/j.ejrad.2016.12.013; PMID: 28034568. 23. Tatabe S, Sugimura K, Aoki T, et al. Multiple beneficial effects of balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension. Circ J 2016;80:980–8. https://doi.org/10.1253/circj.CJ-15-1212; PMID: 26911363. 24. Broch K, Murbraech K, Ragnarsson A, et al. Echocardiographic evidence of right ventricular functional improvement after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant 2016;35:80–6. https://doi.org/10.1016/j. healun.2015.08.007; PMID: 26476768. 25. Ogawa A, Satoh T, Fukuda T, et al. Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: results of a multicenter registry. Circ Cardiovasc Qual Outcomes 2017;10:e004029. https://doi. org/10.1161/CIRCOUTCOMES.117.004029; PMID: 29101270. 26. Yokokawa T, Sugimoto K, Nakazato K et al. Electrocardiographic criteria of right ventricular hypertrophy in patients with chronic thromboembolic pulmonary hypertension after balloon pulmonary angioplasty. Intern Med 2019;58:2139–44. https://doi.org/10.2169/ internalmedicine.2320-18; PMID: 30996169. 27. Nagao M, Yamasaki Y, Abe K, et al. Energy efficiency and pulmonary artery flow after balloon pulmonary angioplasty for inoperable, chronic thromboembolic pulmonary hypertension: analysis by phase-contrast MRI. Eur J Radiol 2017;87:99–104. https://doi.org/10.1016/j.ejrad.2016.12.015; PMID: 28065382. 28. Kreichbaum SD, Wiedenroth CB, et al. N-terminal pro-B-type

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natriuretic peptide for monitoring after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant 2018;37:639–46. https://doi.org/10.1016/j.healun.2017.12.006; PMID: 29329761. VVelázquez M, Albarrán A, Hernández I, et al. Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. observational study in a referral unit. Rev Esp Cardiol (Engl Ed) 2019;72:224–32. https://doi.org/10.1016/j.rec.2018.02.020; PMID: 29857972. Brenot P, Jaïs X, Taniguchi Y, et al. French experience of balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. Eur Respir J 2019;53:1802095. https://doi.org/10.1183/13993003.02095-2018; PMID: 31023842. Siennicka A, Darocha S, Banaszkiewicz M et al. Treatment of chronic thromboembolic pulmonary hypertension in a multidisciplinary team. Ther Adv Respir Dis 2019;13:1753466619891529. https://doi. org/10.1177/1753466619891529; PMID: 31878837. Maschke S, Hinricks J, Renne J et al. C-Arm computed tomography (CACT)-guided balloon pulmonary angioplasty (BPA): evaluation of patient safety and peri- and postprocedural complications. Eur Radiol 2019;29:1276–84. https://doi.org/10.1007/s00330-018-5694-6; PMID: 30209593. Kimura M, Kohno T, Kawakami T, et al. Shortening hospital stay is feasible and safe in patients with chronic thromboembolic pulmonary hypertension treated with balloon pulmonary angioplasty. Can J Cardiol 2019;35:193–8. https://doi.org/10.1016/j.cjca.2018.12.001; PMID: 30760426. Ikeda N, Kubota S, Okazaki T, et al. The predictors of complications in balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. Catheter Cardiovasc Interv 2019;93:e349–56. https://doi.org/10.1002/ ccd.28133; PMID: 30773792. Godinas L, Bonne L, Budts W, et al. Balloon pulmonary angioplasty for the treatment of non-operable chronic thromboembolic pulmonary angioplasty: Single centre experience with low initial complication rate. J Vasc Interv Radiol 2019;30:1265–72. https://doi.org/10.1016/j. jvir.2019.03.023; PMID: 31349979. van Thor M, Lely R, Braams N et al. Safety and efficacy of balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension in the Netherlands. Neth Heart J 2020;28:81–88. https://doi.org/10.1007/s12471-019-01352-6; PMID: 31782109. Johns CS, Swift AJ, Hughes PJC et al. Pulmonary MR angiography and perfusion imaging: a review of methods and applications. Eur J Radiol 2017;86:361–70. https://doi. org/10.1016/j.ejrad.2016.10.003; PMID: 28341390. Renapurkar RD, Bolen MA, Shrikanthan S, et al. Comparative assessment of qualitative and quantitative perfusion with dual-energy CT and planar and SPECT-CT V/Q scanning in patients with chronic thromboembolic pulmonary hypertension. Cardiovasc Diagn Ther 2018;8:414–22. https:// doi.org/10.21037/cdt.2018.05.07; PMID:30214856. Tamura M, Yamada Y, Kawakami T, et al. Diagnostic accuracy of lung subtraction iodine mapping CT for the evaluation of pulmonary perfusion in patients with chronic thromboembolic pulmonary hypertension: correlation with perfusion SPECT/CT. Int J Cardiol 2017;243:538–43. https:// doi.org/10.1016/j.ijcard.2017.05.006; PMID: 28526539. Nagayoshi S, Fujii S, Nakajima T, Muto M. Intravenous ultrasound- guided balloon pulmonary angioplasty in the treatment of totally occluded chronic thromboembolic pulmonary hypertension. EuroIntervention 2018;14:234–5. https://doi.org/10.4244/EIJ-D-17-00770; PMID: 29061549. Kopec´ G, Waligóra M, Sętpniewski J, et al. In vivo characterization of changes in composition of organized thrombus in patient with chronic thromboembolic pulmonary hypertension treated with balloon pulmonary angioplasty. Int J Cardiol 2015;186:279–81. https://doi.org/10.1016/j. ijcard.2015.03.203; PMID: 25828135. Inohara T, Kawakami T, Kataoka M, et al. Lesion morphological classification by OCT to predict therapeutic efficacy after balloon pulmonary angioplasty in CTEPH. Int J Cardiol 2015;197:23–25. https://doi.org/10.1016/j. ijcard.2015.06.036; PMID: 26142960. Inami T, Kataoka M, Shimura N et al. Pressure-wire-guided percutaneous transluminal pulmonary angioplasty a breakthrough in catheter-interventional therapy for chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol Intv 2014;7:1297–306. https://doi.org/10.1016/j. jcin.2014.06.010; PMID: 25459043. Kinutani H, Shinke T, Nakayama K et al. High perfusion pressure as a predictor of reperfusion pulmonary injury after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. Int J Cardiol Heart Vasc 2016;11:1–6. https://doi.org/10.1016/j.

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Balloon Pulmonary Angioplasty https://doi.org/10.1016/j.cjca.2019.01.016; PMID: 30935632. 61. Shimokawahara H, Ogawa A, Mizoguchi H, et al. Vessel stretching is a cause of lumen enlargement immediately after balloon pulmonary angioplasty: intravascular ultrasound analysis in patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2018;11:e006010. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.006010; PMID: 29643129. 62. Taniguchi Y, Brenot P, Jais X, et al. Poor subpleural perfusion predicts failure after balloon pulmonary angioplasty for nonoperable chronic thromboembolic pulmonary hypertension. Chest 2018;154:521–31. https://doi. org/10.1016/j.chest.2018.03.059; PMID: 29730328. 63. Fedullo P, Kerr KM, Kim NH, Auger WR. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2011;183:1605–13. https://doi.org/10.1164/ rccm.201011-1854CI; PMID: 21330453. 64. Wiedenroth CB, Ghofrani HA, Adameit MSD, et al. Sequential treatment with riociguat and balloon pulmonary angioplasty for patients with inoperable chronic thromboembolic pulmonary hypertension. Pulm Circ

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2018;8:2045894018783996. https://doi. org/10.1177/2045894018783996; PMID: 29939102. Mayer E, Jenkins D, Lindner J, et al. Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg 2011;141:702–10. https://doi.org/10.1016/j.jtcvs.2010.11.024; PMID: 21335128. Nakamura M, Sunagawa O, Tsuchiya H, et al. Rescue balloon pulmonary angioplasty under veno-arterial extracorporeal membrane oxygenation in a patient with acute exacerbation of chronic thromboembolic pulmonary hypertension. Int Heart J 2015;56:116–20. https://doi. org/10.1536/ihj.14-257; PMID: 25742948. Yamagata Y, Ikeda S, Nakata T, et al. Balloon pulmonary angioplasty is effective for treating peripheral-type chronic thromboembolic pulmonary hypertension in elderly patients. Geriatr Gerontol Int 2018;18:678–84. https://doi.org/10.1111/ ggi.13224; PMID: 29278287. Yanaka K, Nakayama K, Shinke T, et al Sequential hybrid therapy with pulmonary endarterectomy and additional balloon pulmonary angioplasty for chronic thromboembolic

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pulmonary hypertension. J Am Heart Assoc 2018;7:e008838. https://doi.org/10.1161/JAHA.118.008838; PMID: 29929993. Wiedenroth CB, Olsson KM, Guth S, et al. Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic disease. Pulm Circ 2018;8:2045893217753122. https://doi. org/10.1177/2045893217753122; PMID: 29283044. Inami T, Kataoka M, Kikuchi H, et al. Balloon pulmonary angioplasty for symptomatic chronic thromboembolic disease without pulmonary hypertension at rest. Int J Cardiol 2019;289:116–8. https://doi.org/10.1016/j.ijcard.2019.04.080; PMID: 31060757. Coghlan JG. Balloon pulmonary angioplasty: does it have a role in CTED? Pulm Circ 2018;8:2045893218754887. https:// doi.org/10.1177/2045893218754887; PMID: 29309246. Jin Q, Zhao ZH, Luo Q, et al. Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: state of the art. World J Clin Cases 2020;8:2679–702. https://doi. org/10.12998/wjcc.v8.i13.2679; PMID: 32742980.

Guest Editorial

Extended Statement by the British Cardiovascular Intervention Society President Regarding Transcatheter Aortic Valve Implantation Philip MacCarthy,1 Dave Smith,2 Douglas Muir,3 Daniel Blackman,4 Mamta Buch,5 Peter Ludman,6 Clare Appleby,7 Nick Curzen,8 David Hildick-Smith,9 Neal Uren,10 Mark Turner,11 Uday Trivedi9 and Adrian Banning12 1. King’s College Hospital, London, UK; 2. Morriston Hospital, Swansea, UK; 3. James Cook University Hospital, Middlesbrough, UK; 4. Yorkshire Heart Centre, Leeds, UK; 5. Wythenshawe Hospital, Manchester, UK; 6. University Hospital, Birmingham, UK; 7. Liverpool Heart Centre, Liverpool, UK; 8. Southampton University Hospital, Southampton, UK; 9. Brighton and Sussex University Hospitals, Sussex, UK; 10. Edinburgh Royal Infirmary, Edinburgh, UK; 11. Bristol Royal Infirmary, Bristol, UK; 12. John Radcliffe Hospital, Oxford, UK

Disclosures: The authors have no conflicts of interest to declare. Received: 18 December 2020 Accepted: 6 January 2021 Citation: Interventional Cardiology Review 2021;16:e03. DOI: https://doi.org/10.15420/icr.2021.02 Correspondence: Philip MacCarthy, King’s College Hospital, King’s College London, Strand, London WC2R 2LS, UK. E: philip.maccarthy@nhs.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve implantation (TAVI) has now become the default intervention for severe, symptomatic aortic stenosis (AS) in inoperable and high-risk patients and patients at intermediate risk who are anatomically suitable for the transfemoral approach, under the guidance of a multidisciplinary heart team. Evidence is building for the use of TAVI in low-risk patients and as a result, the number of TAVI procedures in all developed nations is increasing dramatically. The number of TAVI procedures exceeded the number of isolated surgical aortic valve replacements in the US in 2015 and all surgical aortic valve replacements in 2018 according to the latest Transcatheter Valve Therapy Registry data.1 Although the UK is lagging behind most of these nations, the numbers of TAVI procedures is nevertheless increasing year by year. The British Cardiovascular Intervention Society (BCIS) has issued guidance as to how patients with AS should be managed and a service specification as to how TAVI should be performed.2 We hope this will go some way to standardising care across the UK for patients with AS but we are aware that much more needs to be done. BCIS is collaborating with the Valve for Life campaign to analyse inequities in TAVI provision in the UK and we hope to work with NHS commissioners to address this, and to encourage new centres to provide TAVI where local provision is inadequate or impossible with current facilities. The following document forms the basis of what will be a prolonged effort to improve TAVI provision in the UK and standardise its delivery.

1. Introduction Service Specification for TAVI: Recommendations of the British Cardiovascular Intervention Society – Updated July 2019

Severe AS (sAS) is the most common primary valve disease leading to surgery or catheter intervention in Europe and North America, with a growing prevalence due to the ageing population.3 It is a degenerative condition in which the outflow of blood from the heart is restricted by progressive narrowing of the aortic valve. This leads to symptoms of breathlessness, exertional chest pain or blackouts. Untreated, the condition causes left ventricular failure and death, with up to 40% of

patients dying within 1 year of symptom onset. No medical therapy can improve outcome for this condition and therefore valve intervention is the only treatment option that alters prognosis. The standard of care for this condition has historically been surgical aortic valve replacement (sAVR), but around one-third of patients are ineligible for sAVR due to a combination of age and comorbidities. TAVI is a transformational technology; it is a much less invasive approach than sAVR and involves implantation of a new valve without the need for complex surgery or the use of a heart–lung bypass machine. This is most commonly done via the femoral arteries (transfemoral or TF approach), but it may also be accomplished via the subclavian arteries or via minimally invasive access using the cardiac apex between the ribs, directly into the aorta through a small incision. Less common approaches via the carotid arteries, axillary artery and the femoral veins or abdominal aorta have also been described. Therefore, for most patients undergoing TAVI, the procedure is performed via the femoral artery, under local anaesthesia or conscious sedation in a catheter laboratory. This results in quicker patient recovery, a shorter hospital stay and reduced use of expensive and limited resources such as cardiac operating theatres and intensive care unit beds, as well as postoperative nursing care. A number of different valve designs are available, including balloonexpandable and self-expandable devices. Each has different performance characteristics, which may be tailored to specific anatomical or patientspecific features. TAVI has been proven to be superior to medical therapy for inoperable patients and superior to sAVR in patients who are high risk for sAVR (Society of Thoracic Surgeons [STS] or Euroscore II >8%).4–6 Trials have also shown that patients with intermediate surgical risk (STS or Euroscore II >4%) who are eligible for a TF approach have superior outcomes with TAVI.7–9 Moreover, randomised trials have shown TAVI to be superior to sAVR in patients classified as low risk (STS <4), with outcome data so far published to 12 months.10,11

BCIS TAVI Statement 2. Entry to Care Pathway

Indications for aortic intervention by means of TAVI or sAVR include sAS and any of the following: 1. 2. 3. 4.

symptoms related to sAS; left ventricular dysfunction related to sAS; evidence of very severe AS, or rapid increase in echo severity; abnormal exercise test or elevated cardiac biomarkers (B-type natriuretic peptide); 5. severe bioprosthetic valve failure. After appropriate investigations including (but not limited to) transthoracic echocardiography and cardiac–peripheral CT, patients should be discussed by an appropriately constituted multidisciplinary heart team (MDT; the Heart Team) as per the British Cardiovascular Society (BCS), and Society for Cardiothoracic Surgery (SCTS) and BCIS guidelines.12 After taking into account age, frailty and comorbidities, MDT outcome will be: 1. sAVR; 2. TAVI; 3. conservative/medical management. Recommendations 1 or 2 will be made by taking into account the cardiac and extracardiac characteristics of the patient, and the individual risk of surgery (which is assessed by the judgement of the Heart Team), in addition to risk scoring and the technical and anatomical feasibility of TAVI. Validated calculators of conventional surgical risk (e.g. Euroscore II or STS score) have several limitations in selecting patients for TAVI and are now generally not used clinically.4 Specifically, they do not assess frailty, degree of disability, echocardiographic and anatomical features or important comorbidities. Therefore, patient selection for TAVI requires consideration of the whole patient as well as several prognostic variables.

Given the time dependency of treatment in the outcome of patients with sAS, it is vital that after MDT discussion, recommended therapy should be offered promptly (section 8a). AS has an extremely poor prognosis and patients will die on the waiting list for treatment. BCIS recommends that regular review of mortality of patients on waiting lists is performed by all TAVI centres. The absolute maximum waiting time from point of referral to the definitive valve procedure should be 18 weeks.

3. MDT Structure

Each MDT should involve a minimum of one TAVI interventionist, one cardiac surgeon and one imaging or general cardiologist and should have appropriate administrative support.13 Direct MDT input from other specialties (elderly care medicine, anaesthetics) will be required for some patients, and local pathways should be developed to ensure that this input is available quickly. MDT meetings should occur at least weekly or sufficiently frequently to ensure that unnecessary delays do not occur. Arrangements should also be put in place for ad hoc MDT discussion of urgent patients who may present between formal MDT meetings. Adequate documentation with dissemination of decisions should be prioritised. Several studies have demonstrated the importance of the TAVI clinical nurse specialist/coordinator, which BCIS considers a mandatory component of the Heart Team (MDT) and every TAVI centre.

4. Follow-up Post-intervention

Following TAVI and at the point of discharge, the implanting team should document the recommended medical therapy and set out arrangements for further follow-up. The first follow-up visit should be within 6–8 weeks in order to assess any possible adverse effects of treatment. This will usually be with the implanting centre. Subsequent follow-up arrangements should be according to guidelines for bioprosthetic valve intervention (usually annually with echocardiographic assessment).4 Patients can be followed up by their local cardiology service after the first review at the TAVI centre.

Technical aspects that may favour TAVI or sAVR should be assessed by detailed review of all investigations. Technical factors for potential TAVI should include suitability for TF access (which is associated with the lowest risk) and risk factors for adverse events, such as coronary occlusion, annular trauma and paravalvular leak. Additional adverse features for sAVR that are not represented in surgical calculators should be noted. These include presence of severe aortic calcification, liver disease, chest wall deformity and previous thoracic radiotherapy.

5. Interdependence with Other Services

Medical management may be recommended when comorbidities and frailty are so severe that no improvement in quality of life or prognosis is expected from intervention, i.e. intervention is thought to be futile. Therefore, the MDT should refer to reports from other specialists with regard to prognosis and severity of other conditions. This may include memory clinic assessments for patients with cognitive impairment, given that significant dementia is likely to negate any benefit from intervention.

The MDT should refer to up-to-date guidelines on valve intervention (e.g. National Institute for Health and Care Excellence [NICE], European Society of Cardiology and European Association for Cardio-Thoracic Surgery [ESC/EACTS] 2017 guidelines for the management of valvular heart disease) in order to inform decision-making.3 This is especially important, given that this is a rapidly evolving literature, and that there are several trials in different patient groups underway that will further advance the evidence base for therapy.

The BCIS recommends that TAVI centre essential on-site services should fulfil the following criteria: a. b.

MDT. Constituted as above (section 3). Imaging. A sophisticated echo and CT service is essential for procedural planning, vascular access assessment and valve sizing. At least one consultant should be assigned to the Heart Team to lead the imaging aspect of the service. ITU. An on-site ITU is mandatory in order to manage multi-system dependence or complications of the procedure. In this regard, on-site access to renal replacement therapy is required. Cardiac surgery. Emergency cardiac surgery for complications is uncommon during TF TAVI, with the latest registry data of 27,760 patients in Europe suggesting an incidence of <1%.14 Although infrequent, the commonest complications requiring emergency surgical bailout include left ventricular perforation by guidewire and annular rupture, which are immediately life threatening and can only be successfully treated with immediate surgery. Therefore, on-site cardiac surgery is an absolute requirement to support a TAVI service and is recommended by ESC/EACTS and North American guidelines.15 TAVI via thoracic approaches (e.g. transapical, direct aortic) are led by cardiac surgeons. Vascular/interventional radiology/vascular surgery. Vascular complications are the commonest adverse events during TF TAVI,

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BCIS TAVI Statement

therefore robust emergency arrangements are needed to deal with these. Vascular bailout may be performed by open surgery or percutaneous techniques. Vascular interventional radiology and vascular surgery expertise should be immediately available, with access to equipment and techniques for percutaneous management of complications (occlusion balloons, guidewires and peripheral stents) or open vascular surgery as needed. TAVI centres should have a local standard operating policy for these clinical events to ensure that emergencies are managed effectively and that systems are reviewed and updated frequently. TAVI clinical nurse specialist and administrative support. BCIS considers a coordinating TAVI clinical nurse specialist an essential component of the TAVI team. Administrative support should also be provided for an effective MDM (section 3).

6. Expected Significant Future Demographic Changes

In keeping with the degenerative nature of the condition, the ageing population will require an increase in TAVI implantation rates. In addition, newer data suggest the efficacy of TAVI (versus sAVR) across the spectrum of risk in patients with AS, including studies in patients at low surgical risk who currently undergo sAVR.11,12

7. Current Evidence Base for TAVI in Treating Severe Aortic Stenosis

Several large randomised controlled trials have been published, which may be briefly summarised as follows:

• Inoperable or extreme-risk patients: TAVI superior to medical therapy

(PARTNER 1B trial).5 • High-risk patients (mortality risk >8%): TF TAVI non-inferior or superior to sAVR (CoreValve high-risk study, PARTNER A trial).6,7,16 • Intermediate-risk patients (mortality risk >4% and <8%): TF TAVI non-inferior or superior to sAVR (PARTNER 2 trial, SURTAVI, NOTION).7–9 • Low risk: TF TAVI superior to sAVR in patients at low risk (STS < 4; PARTNER 3 follow-up to 12 months to date10 or equivalent in this patient population; Evolut low-risk trial).11 These data have been reviewed extensively in the production of the updated ESC/EACTS 2017 guidelines,but unfortunately several more trials have been published since the guidelines publication, rendering them already out of date.3

8. British Cardiovascular Intervention Society TAVI Pathway Recommendations

The goal of therapy is to offer eligible patients with sAS timely intervention to prevent premature death, improve symptoms and reduce hospitalisation, using a transformational, minimally invasive treatment allowing rapid return to improved quality of life. BCIS proposes the following guidelines: a. TAVI pathway – maximum 18 weeks: 1.

Carroll JD, Mack MJ, Vemulapalli S, et al. STS-ACC TVT Registry of Transcatheter Aortic Valve Replacement. J Am Coll Cardiol 2020;76:2492–516. https://doi.org/10.1016/j. jacc.2020.09.595; PMID: 33213729. 2. BCIS. British Cardiovascular Intervention Society. Service Specification for Transcatheter Aortic Valve Implantation. 2020. https://www.bcis.org.uk/resources/bcis-guidancedocuments/service-specification-for-transcatheter-aortic-

• referral to clinic <6 weeks; • clinic to investigations and MDT discussion <6 weeks; • MDT decision to TAVI <6 weeks. Regular local audit of service performance should be performed, including quality improvement projects and waiting list surveillance. b. TAVI volume per centre and operator: there is now published evidence to support improved outcomes with TAVI centre and operator volume:15

• new centres should aim for 50 cases per year for two operators during their learning curve;

• the aim of every centre should be for at least 100 cases/year – that

is, 50 cases/operator done as first in established centres to ensure volume experience and skill in more than one device; • the TAVI procedure should be performed by two appropriately trained TAVI operators. c. General anaesthesia versus non-general anaesthesia: centres should aim for >90% cases non-GA. d. Length of stay: 1–5 days. Level 3 beds should be used only in exceptional cases. e. TAVI data submission: the full UK TAVI dataset for all TAVI procedures should be submitted to the National Institute for Cardiovascular Outcomes Research (NICOR) at least every quarter, with data for one quarter to be submitted by the end of the following quarter. Thirty-day mortality, stroke rate and vascular complications (as per VARC [Valve Academic Research Consortium] criteria) will be monitored (observed versus predicted) using the NICOR TAVI mortality model/funnel plots. Details of all TAVI procedures and their outcomes are submitted to NICOR. Criteria for defining outlier performance are currently being agreed, but it is expected that the BCS outlier policy will be used to implement Society advice. At present, 30-day mortality and major complications including rate of vascular complications or stroke are used to measure safety. However, other outcomes such as change in symptoms and quality of life may be used in the future. Currently all departments receive performance outcomes adjusted for risk with funnel plots.

Applicable Obligatory National/ European Standards Applicable Obligatory National Standards

NICE IPG586: Transcatheter aortic valve implantation for aortic stenosis. July 2017.17

Other Applicable Standards to be Met by Commissioned Providers

Adherence to ESC/EACTS 2017 guidelines for the management of valvular heart disease or subsequent updates.3 valve-implantation-tavi (accessed 11 February 2021). 3. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. https://doi.org/10.1093/ eurheartj/ehx391; PMID: 28886619. 4. Leon MB, Smith CR, Mack M, et al. Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607.

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https://doi.org/10.1056/NEJMoa1008232; PMID: 20961243. 5. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. https://doi.org/10.1056/ NEJMoa1103510; PMID: 21639811. 6. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790–8. https://doi.org/10.1056/

BCIS TAVI Statement NEJMc1408396; PMID: 25184874. Thyregod HGH, Steinbrüchel DA, Ihlemann N, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis. 1-year results from the all-comers NOTION randomized clinical trial. J Am Coll Cardiol 2015;65:2184–94. https://doi.org/10.1016/j. jacc.2015.03.014; PMID: 25787196. 8. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. https://doi. org/10.1056/NEJMoa1514616; PMID: 27040324. 9. Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediate-risk patients. N Engl J Med 2017;376:1321–31. https://doi. org/10.1056/NEJMoa1700456; PMID: 28304219. 10. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aorticvalve replacement with a balloon-expandable valve in lowrisk patients. N Engl J Med 2019;380:1695–705. https://doi. 7.

org/10.1056/NEJMoa1814052; PMID: 30883058. 11. Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aorticvalve replacement with a self-expanding valve in low-risk patients. N Engl J Med 2019;380:1706–15. https://doi. org/10.1056/NEJMoa1816885; PMID: 30883053. 12. Joint Statement on clinical selection for trans-catheter aortic valve implantation (TAVI) 1/8/2017 on behalf of BCS, SCTS and BCIS. https://www.bcis.org.uk/wp-content/ uploads/2017/08/TAVI-commissioning-statement-final.pdf (accessed 11 February 2021). 13. Eggebrecht H, Vaquerizo B, Moris C, et al. Incidence and outcomes of emergent cardiac surgery during transfemoral transcatheter aortic valve implantation (TAVI): insights from the European Registry on Emergent Cardiac Surgery during TAVI (EuRECS-TAVI). Eur Heart J 2018;39:676–84. https://doi. org/10.1093/eurheartj/ehx713; PMID: 29253177. 14. Otto CM, Kumbhani DJ, Alexander KP, et al. 2017 ACC expert consensus decision pathway for transcatheter aortic valve

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replacement in the management of adults with aortic stenosis: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2017;69:1313–46. https://doi.org/10.1016/j. jacc.2016.12.006; PMID: 28063810. 15. Vemulapalli S, Carroll J, Mack M, et al. Procedural volume and outcomes for transcatheter aortic valve replacement. N Engl J Med 2019;380:2541–50. https://doi.org/10.1056/ NEJMsa1901109; PMID: 30946551. 16. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. https://doi.org/10.1056/ NEJMoa1103510; PMID: 21639811. 17. National Institute for Health and Care Excellence. Transcatheter aortic valve implantation for aortic stenosis: Interventional procedures guidance [IPG586]. London: NICE; 2017. https://www.nice.org.uk/guidance/ipg586 (accessed 11 February 2021).

Structural

Keywords

Aortic stenosis, transcatheter aortic valve insertion, transcatheter aortic valve replacement, aortic valve replacement, health economics, British Cardiovascular Intervention Society guidelines Disclosure: DS is a proctor for Edwards Lifesciences. CM has no conflicts of interest to declare. Received: 3 February 2020 Accepted: 8 June 2020 Citation: Interventional Cardiology Review 2021;16:e04. DOI: https://doi.org/10.15420/icr.2020.03 Correspondence: David Smyth, Department of Cardiology, Christchurch Hospital, Private Bag 4710, Christchurch 8140, New Zealand. E: david.smyth@cdhb.health.nz Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In The Structure of Scientific Revolutions, Thomas Kuhn, the American philosopher of science, argued that scientific advances occur by revolution when the dominant scientific theory of the day is lacking and is rapidly replaced by a new radical theory.1 For example, the European voyages to the Americas in the 15th and 16th centuries required accurate navigation. The prevalent geocentric view at the time, that the celestial bodies circled the Earth, was woefully inaccurate as a basis for transatlantic navigation. Accordingly, the geocentric view was overthrown and rapidly superseded by the heliocentric view put forward by Copernicus, which provided much more accurate navigation. There was, to use Kuhn’s terminology, a paradigm shift. As with all revolutions, there were casualties. The imprisonment of Galileo is well known, but Michael Servetus (who is credited with describing pulmonary circulation before William Harvey) was burned at the stake under Calvin’s orders, partly for embracing this idea. The recent trials in transcatheter aortic valve implantation (TAVI) have resulted in a paradigm shift away from surgical aortic valve replacement (sAVR) as the gold standard definitive therapy in the treatment of aortic stenosis.2–8 It seems that a revolution is underway in the treatment of aortic stenosis, but hopefully without imprisonments or burnings.

Background

Aortic stenosis is a common condition affecting about 4–5% of the population aged 65 years.9 sAVR has traditionally been the mainstay of treatment, but over the past decade, a number of landmark studies have demonstrated that TAVI is a viable alternative.2–8 Such is the rapidity at which new information is becoming available, guidelines become outdated almost as soon as they are written. The mounting data are compelling, TAVI is at least as effective as sAVR in treating aortic stenosis, and quite likely superior in the short term.2–8 Minor concerns exist around the increased requirement for permanent pacing and subsequent coronary access if coronary disease supervenes, particularly if younger patients are to be treated. Moreover, there are no long-term data about valve durability, but this must be balanced by a paucity of data on the durability of most surgical bioprostheses. Such is

the appeal of TAVI amongst patients and their referrers, that even if transcatheter valves were ultimately shown to be less durable, it is likely that many patients would still prefer TAVI to avoid a thoracotomy and a longer recovery time. New Zealand, like the UK, has a comprehensive taxation-funded health service, and like the British, New Zealanders are proud of the services it provides. In fact, the New Zealand system is older than the UK National Health Service. It was introduced in 1938 by the first New Zealand Labour government, who envisaged free healthcare for all. While there are subtle differences between the New Zealand Heath Service and the National Health Service, they share the same basic philosophy; that treatment is provided based on need and free at the point of delivery. In fact, universally free healthcare has never been totally achieved in New Zealand. GP visits, for example, are only partially funded and attract a copayment from the patient. The land mass of New Zealand is about the same as that of the UK. The population is considerably smaller, around 5 million. This population is geographically dispersed, and health is coordinated by 19 District Health Boards (DHBs), which are semi-autonomous. Interventional cardiology procedures are provided in 10 DHBs, whereas TAVI and cardiothoracic surgery are provided in five (Auckland, Waikato, Wellington, Christchurch and Dunedin). There are mature hub and spoke relationships between these tertiary centres and the populations of smaller towns. The landmark randomised trials have advanced our understanding of who should receive TAVI to treat aortic stenosis. Given the fact that these trials were performed by high-volume operators in tertiary institutions, they also inform us where they should be performed and by whom. The recently published British Cardiovascular Intervention Society Service Specification for TAVI is an important addition to the literature. It recommends that TAVI should take place in large tertiary centres with onsite cardiac surgery, interventional radiology, intensive treatment unit and

Providing Transcatheter Valves in the Public Health System the like, so that in the rare case where a complication occurs, immediate help is available. In countries, such as the UK and New Zealand, that have public healthcare funding, this means the large tertiary public hospitals. These are the institutions that employ cardiologists with the required skills and provide enough suitable patients on which these skills can be maintained. There is an obvious benefit of coordinating TAVI through large publicly funded institutions.

Current Obstacles

Undoubtedly, public health systems do ‘large’ very well. However, there are notable downsides to the way large public hospitals operate, given the fact they are invariably resource constrained. Public systems are cumbersome and not agile enough to change funding streams at short notice, even when compelling evidence of an alternative emerges. In New Zealand, the public health system is struggling to adapt to a sudden change in treatment paradigm, as is dictated by the low-risk TAVI trials.6–8 In New Zealand, budgets are set based on existing activity (i.e. current sAVR volume), and are allocated by service, rather than pathology. Any changes to this will take both time and skilful diplomacy. Theatre staff and surgeons are already employed on lifelong contracts, and it would be untenable to terminate their employment. It would be difficult to redeploy cardiac surgeons as TAVI interventionists without considerable and lengthy retraining. The skillsets of cardiologists and cardiac surgeons are markedly different. Cardiac surgeons will undoubtedly continue to be employed by public hospitals and be freed up to perform other procedures. It is ironic that the legacy of the landmark studies may result in faster surgery for patients with lung cancer, and longer waiting times for TAVI patients in public hospitals. TAVI patients rarely require an intensive treatment unit bed, and have shorter hospital stays and fewer subsequent readmissions compared with patients undergoing sAVR. Accordingly, it has been shown in the US healthcare system that TAVI is cheaper than sAVR, despite the higher cost of the prosthesis.10 It seems very likely that TAVI will be a cheaper option in publicly funded health systems too. On the face of it, a simple solution to facilitate an expansion in TAVI volumes would be to transfer funding from sAVR. However, as mentioned above, it may not be so simple to achieve this in publicly funded systems in the short term. The reduced costs demonstrated by Baron et al. relate simply to the costs of the procedure and subsequent care.10 They do not include new costs, such as those required to commission additional facilities and employ staff. Existing catheter laboratories in New Zealand are already stretched performing other interventional work. Wait times in our centre for elective coronary or electrophysiology procedures can be some months, and this is similar around the country. Even acute procedures are delayed, with the most recent data from the All New Zealand Acute Coronary Syndrome Quality Improvement Programme registry suggesting only 71% of those patients who have angiograms for non-ST segment elevation MI are performed within 72 hours (the maximum acceptable wait time recommended by the European Society of Cardiology guidelines).11,12 This compares favourably with 57% in the UK, but quite poorly with 92% in the US, where resource constraint is less of an issue.13,14 There is limited spare 1.

Kuhn T. The Structure of Scientific Revolutions. Chicago, IL: University of Chicago Press, 1962. 2. Smith C, Leon M, Mack M, et al. PARTNER Trial Investigators. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. https:// doi.org/10.1056/NEJMoa1103510; PMID: 21639811. 3. Adams D, Popma J, Reardon M, et al. Transcatheter aorticvalve replacement with a self-expanding prosthesis. N Engl J

capacity in the public system to perform extra TAVIs. To increase volumes, extra catheter laboratories may need to be commissioned and trained structural interventionalists employed. Any funding would have to compete with other worthy treatments; for example, cancer and mental health. The classic response of constrained systems is to rigidly cap volumes, and two of the DHBs offering TAVI in New Zealand have done this. In the other three, the decision to treat a patient with aortic stenosis with one modality rather than another is made by a multidisciplinary team in line with the British Cardiovascular Intervention Society service specification document. It may appear that these DHBs are enlightened, but without increased infrastructure, the waiting lists have grown in these centres. Currently, there is little hope that patients can receive TAVI within 18 weeks of referral, as recommended in the British Cardiovascular Intervention Society service specification document. Whereas previously, a person may have received timely sAVR, the increased time to wait for TAVI may offset any advantage shown by randomised trials. However, such is the success of TAVI that patients and referring cardiologists are reluctant to consider surgery. There is a danger that hard-pressed DHBs will be forced to outsource TAVI volumes to smaller private institutions to reduce waiting times. Alternatively, the DHBs could insist that patients with aortic stenosis continue to be treated by sAVR. This will increase the cost of the treatment and may lead to a reduction in quality of outcomes.

Conclusion

TAVI is disruptive, dominant and revolutionary technology. It ameliorates aortic stenosis with better outcomes, at a lower cost and with more rapid recovery than sAVR. While it is not the panacea for all aortic valve ills, the recent evidence suggests that many patients who would have previously undergone sAVR for aortic stenosis could be treated with TAVI. It would be a shame if public systems could not offer it to suitable patients. Cardiologists can certainly advocate for more funding and transfer of resources. However, as a community, we should also look at our own practice and the other procedures that we perform. Do we need to be conducting so many percutaneous coronary interventions for patients with stable coronary disease or pulmonary vein isolations for AF?15–17 We must not lose sight of the fact that the most important part of this revolution is the person with aortic stenosis. Without major change in practice, or a windfall in funding, it is difficult to see how a publicly funded health system will cope with the increasing workload, and patients with this lethal condition will not receive the best treatment. In the short term, this might mean continuing sAVR for some low-risk patients, to avoid patients coming to harm by waiting on a long TAVI list. In the medium term, funding should be diverted from sAVR into TAVI programmes, with the aim that appropriate patients are given the best treatment according to the scientific studies. Careful consideration is required, and urgent dialogue necessary between clinicians, funders and providers to facilitate a peaceful revolution. Without this, there may be imprisonment and burnings at the stake.

Med 2014;370:1790–8. https://doi.org/10.1056/ NEJMoa1400590; PMID: 24678937. 4. Leon M, Smith C, Mack ,M et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. https://doi.org/10.1056/ NEJMoa1514616; PMID: 27040324. 5. Reardon M, Van Mieghem N, Popma J, et al. Surgical or transcatheter aortic-valve replacement in intermediate-risk

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patients. N Engl J Med 2017;376:1321–31. https://doi. org/10.1056/NEJMoa1700456; PMID: 28304219. 6. Thyregod H, Ihlemann N, Jørgensen T, et al. Five-year clinical and echocardiographic outcomes from the NOTION randomized clinical trial in patients at lower surgical risk. Circulation 2019;139:2714–23. https://doi.org/10.1161/ CIRCULATIONAHA.118.036606; PMID: 30704298. 7. Popma J, Deeb G, Yakubov S, et al. Transcatheter aortic-

Providing Transcatheter Valves in the Public Health System

10.

11.

valve replacement with a self-expanding valve in low-risk patients. N Engl J Med 2019;380:1706–15. https://doi. org/10.1056/NEJMoa1816885; PMID: 30883053. Mack M, Leon M, Thourani V, et al. Transcatheter aorticvalve replacement with a balloon-expandable valve in lowrisk patients. N Engl J Med 2019;380:1695–705. https://doi. org/10.1056/NEJMoa1814052; PMID: 30883058. Baumgartner H, Walther T. Aortic stenosis. In: Camm J, Lüscher T, Maurer G, Serruys P, eds. ESC CardioMed. 3rd ed. Oxford: Oxford University Press, 2018. https://doi. org/10.1093/med/9780198784906.003.0766. Baron S, Wang K, House J, et al. Cost-effectiveness of transcatheter versus surgical aortic valve replacement in patients with severe aortic stenosis at intermediate risk. Circulation 2019;139:877–88. https://doi.org/10.1161/ CIRCULATIONAHA.118.035236; PMID: 30586747. Kerr A, Williams M, Harding S, et al. The All New Zealand Acute Coronary Syndrome Quality Improvement Programme:

implementation, methodology and cohorts (ANZACS-QI). N Z Med J 2016;129:23–36. PMID: 27507719. 12. Roffi M, Patrono C, Collet J, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2016;37:267–315. https://doi.org/10.1093/eurheartj/ ehv320; PMID: 26320110. 13. Weston C, Khambhaita D, Rai S, Shote A. Myocardial Ischemia National Audit Project 2019 Summary Report (2017/18 data). 2019. https://www.nicor.org.uk/nationalcardiac-audit-programme/myocardial-ischaemia-minapheart-attack-audit (accessed 6 July 2020). 14. Hansen C, Wang T, Chen A, et al. Contemporary patterns of early coronary angiography use in patients with non-STsegment elevation myocardial infarction in the United States: insights from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry. JACC Cardiovasc Interv

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2018;11:369–80. https://doi.org/10.1016/j.jcin.2017.12.016; PMID: 29471951. 15. Rasha Al-Lamee R, Thompson D, et al. Percutaneous coronary intervention in stable angina (ORBITA): a doubleblind, randomised controlled trial. Lancet 2018;391:31–40. https://doi.org/10.1016/S0140-6736(17)32714-9; PMID: 29103656. 16. Maron D, Hochman J, Reynolds H, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395–1407. http://doi.org/10.1056/ NEJMoa1915922; PMID: 32227755. 17. Packer D, Mark D, Robb R, et al. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA 2019;321:1261–74. http://doi.org/10.1001/jama.2019.0693; PMID: 30874766.

Coronary

Frailty Scores and Their Utility in Older Patients with Cardiovascular Disease Kenneth Jordan Ng Cheong Chung ,1,2 Chris Wilkinson,1 Murugapathy Veerasamy3,4 and Vijay Kunadian

1,2

1. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 2. Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundations Trust, Newcastle upon Tyne, UK; 3. Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK; 4. Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, UK

Abstract

The world’s population is ageing, resulting in more people with frailty receiving treatment for cardiovascular disease (CVD). The emergence of novel interventions, such as transcatheter aortic valve implantation, has also increased the proportion of older patients being treated in later stages of life. This increasing population burden makes the assessment of frailty of utmost importance, especially in patients with CVD. Despite a growing body of evidence on the association between frailty and CVD, there is no consensus on the optimal frailty assessment tool for use in clinical settings. Previous studies have shown limited concordance between validated frailty instruments. This review evaluates the evidence on the utility of frailty assessment tools in patients with CVD, and the effect of frailty on different outcomes measured.

Keywords

Frailty assessment, older patients, cardiovascular disease, CHD, valvular heart disease, interventional cardiology Disclosure: The authors have no conflicts of interest to declare. Received: 31 May 2020 Accepted: 9 December 2020 Citation: Interventional Cardiology Review 2021;16:e05. DOI: https://doi.org/10.15420/icr.2020.18 Correspondence: Vijay Kunadian, Translation and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, 4th Floor William Leech Building, Queen Victoria Rd, Newcastle upon Tyne NE2 4HH, UK. E: vijay.kunadian@newcastle.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Frail originates from the French word frêle, meaning ‘of little resistance’, and from the Latin word fragilis, meaning ‘easily broken’. In medicine, frailty is a condition in which there is a decline in biological reserves and deterioration in physiological mechanisms that render a person vulnerable to a range of adverse outcomes.1 It is expected that the proportion of the world’s population over 60 years of age will nearly double from 2015 to 2050.2 Alongside this ageing population, an increased burden of frailty means that optimal clinical management of this vulnerable population is of key importance. In recent years, there has been increasing interest in the clinical implications of frailty in patients with cardiovascular disease (CVD). There has also been an increase in the number of patients with frailty, which coexists in up to 60% of patients with CVD.3 Following stressors such as acute coronary syndrome (ACS) and invasive procedures, patients with frailty are at risk of disadvantaged health outcomes, such as dependency, disability, falls, institutionalisation and mortality.4–7 More recently, the coronavirus disease 2019 (COVID-19) pandemic has put an additional stress on these patients, emphasising the importance of frailty assessment to help individualise care for older patients with CVD.8 Frailty and disability, although interrelated, are considered distinct clinical entities. Frailty predicts disability, but disability may exacerbate frailty,5 which may lead to co-occurrence and difficulty in the assessment of frailty. As such, frailty assessment is still not routinely conducted in cardiology practice, and there is a lack of consensus on which frailty assessment tool to use and in which setting.9

This review summarises the latest evidence on common assessment tools used in people with CVD, with a particular focus on those patients with coronary and valvular diseases, and provides a synthesis of the utility of these tools in predicting outcomes in patients with CVD.

Assessment of Frailty

The concept of frailty has been described in various ways. A study identified 67 instruments that can be used to assess frailty.10 Some of these instruments focus on physical and biological aspects, whereas others focus more holistically on physical, psychological and social domains. The commonly used frailty instruments discussed in this review, and the components they evaluate, are summarised in Table 1. Of note, mobility is assessed in all the multidomain tools.

Physical Frailty Phenotype or Fried’s Frailty Scale

The physical frailty phenotype, also called Fried’s frailty scale, consists of five core domains: slowness, weakness, low physical activity, exhaustion and shrinking.4 Patients meeting one or two criteria are considered as pre-frail, and those meeting three or more are considered frail. The physical frailty phenotype formed the basis of the Cardiovascular Health Study (CHS) frailty assessment and is the most frequently used instrument. Although Fried’s scale accurately predicts mortality in patients with CVD, it is not readily measurable in acute clinical situations because it includes a measurement of grip strength, a walking test and a detailed quality of life questionnaire.11

Frailty Scores and CVD Table 1: Frailty Assessment Tools Fried Scale

Frailty Index

Edmonton Frail Scale

Nutritional

Physical activity

Mobility

Strength

Energy

Short Physical SHARE-FI Performance Battery

Tilburg Frailty Indicator

Clinical Frailty Scale

Mood

Social aspect

Disability

Gait Speed

Handgrip Strength

Y Y

Resistance

Demographics General health

Green Score

Cognition

Medication

FRAIL Scale

Y Y

Balance

Y Y

FRAIL = Fatigue, Resistance, Ambulation, Illnesses and Loss of weight; SHARE-FI = Survey of Health Ageing and Retirement in Europe Frailty Index; Y = component present.

Short Physical Performance Battery

The Short Physical Performance Battery (SPPB) measures a series of three timed physical performance tests, including gait speed, chair rises and tandem balance.12 Performance on each test is scored from 0 to 4, with a total score ≤5 (of a possible 12) indicating frailty. The SPPB is relatively simple, cheap and takes approximately 10 minutes to complete. It does not require the presence of physicians, but may be difficult to administer in acute situations.

Frailty Index or Deficit Accumulation Index

The Frailty Index (FI), also known as the Deficit Accumulation Index (DAI), considers frailty across multiple domains and may include physical, psychological and social components in addition to laboratory values.13 The number of deficits identified in an individual is correlated with the level of frailty. The proportion of deficits over the number of items evaluated is expressed as a fraction, and an FI >score 0.25 is usually considered as frail.14

Survey of Health Ageing and Retirement in Europe Frailty Index

The Survey of Health Ageing and Retirement in Europe Frailty Index (SHARE-FI) is based on the Fried criteria, and evaluates exhaustion, appetite, ambulation, resistance, physical activity and handgrip strength measurement.15 The SHARE-FI is easier to measure than the original Fried scale, because the questionnaire can be easily completed at the bedside and does not require the measurement of gait speed.

Tilburg Frailty Indicator

The Tilburg Frailty Indicator is a multidimensional structured questionnaire that evaluates the physical, psychological and social domains.16 It consists of two parts. Part A has 10 questions on frailty determinants (age, sex, marital status, education level, social circumstances and lifestyle). Part B has 15 frailty elements across three domains: 1. Physical, consisting of eight items (physical health, unintentional weight loss, difficulty walking and problems with balance, hearing, vision, hand strength and physical tiredness).

2. Psychological, consisting of four items (cognition, depression, anxiety and coping). 3. Social, consisting of has three items (living alone, social relationships and social support). Each item in Part B scores 1 point, and patients are considered frail if they score at least 5 of a possible 15.

Clinical Frailty Scale

The Clinical Frailty Scale (CFS) was designed for the CSHA and can be readily administered in most clinical settings.17 The CFS is based on fitness, active disease, activities of daily living (ADL) and cognition, and the expanded scale ranges from 1 (very fit) to 9 (terminally ill).17,18 Because assessment relies upon the subjective judgement of a clinician, the measure is prone to interobserver variability.17

Edmonton Frail Scale

The Edmonton Frail Scale (EFS) is another multidimensional scale, comprising 10 domains with 17 potential deficits covering cognition, general health status, functional independence, social support, medication use, nutrition, mood, continence and functional performance.19 The EFS includes the clock test for assessment of cognitive impairment, and the Timed Get Up and Go (TUG) for balance and mobility. The cut-off point for frailty is 12 or more deficits. The EFS has good correlation with the opinion of a specialist following a Comprehensive Geriatric Assessment (CGA).19 Because a CGA is time consuming, the EFS offers a rapid screening tool for the non-geriatric specialist.

Reported Edmonton Frail Scale

The Reported Edmonton Frail Scale (REFS) includes nine frailty domains: cognition, general health status, functional independence, social support, medication use, nutrition, mood, continence and functional performance.20 Compared with the EFS, the REFS is based on self-reported functioning, and is appropriate in patients able to complete a questionnaire. Frailty is identified by a score of at least 8.

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Frailty Scores and CVD Hospital Frailty Risk Score

The Hospital Frailty Risk Score (HFRS) uses ICD-10 diagnostic codes from electronic healthcare records to identify frailty. It includes more than 100 variables derived from routinely collected data and has been validated against both the Fried scale and other FI measures.21

Fatigue, Resistance, Ambulation, Illnesses and Loss of Weight Scale

The Fatigue, Resistance, Ambulation, Illnesses and Loss of weight (FRAIL) scale is a brief, interview-based screening tool. The FRAIL scale is commonly used in the acute setting because it does not include items that are difficult to measure (e.g., walk speed, handgrip strength, stand-up test).22

Comprehensive Geriatric Assessment

The CGA is considered to be the gold standard for frailty assessment and involves a holistic, multidimensional and interdisciplinary assessment of an individual, culminating in the formulation of an individualised management plan.23 The CGA is time consuming and is not part of the routine care of older people. Potentially useful brief screening tests include measuring 5 m gait speed, which is highly predictive of cardiovascular mortality, or handgrip strength.24–27 These frailty assessment tools are all different. Some scales, such as the FRAIL scale, FI and CFS, are based on interviews without objective assessment of physical performance and have a prognostic implication in patients with ACS.28

Frailty and Cardiovascular Disease

The association between frailty and CVD is bidirectional, because frailty is associated with an increased risk of CVD and CVD mortality,11,29 and CVD is associated with an up to threefold increase in frailty.3,30,31 Insights from the CHS have shown that subclinical CVD measures strongly predict frailty, even after adjustment for traditional CVD risk factors, whereas being overweight or obese and having a higher age-adjusted composite coronary artery score in midlife were associated with frailty 26 years later.32,33 This implies that frailty and CVD may also have long-term connections that should be recognised. A meta-analysis by Veronese et al. of 31,343 patients from 18 studies evaluated the prevalence and incidence of CVD according to frailty status.11 Most of the patients were community-dwellers in Europe. Veronese et al. found that frailty and prefrailty were associated with a greater chance of having CVD, with adjusted ORs of 2.85 (95% CI [2.29– 3.53]) and 1.63 (95% CI [1.39–1.91]), respectively.11 Frailty, which was found in 17.9%, was associated with an increased risk of CHD, heart failure and risk of cardiovascular mortality, whereas prefrailty carried a higher risk of heart failure and cardiovascular mortality.11 Supplementary Table 1 summarises studies assessing the outcomes of patients with frailty and CVD. Three components of a modified Fried scale, namely low energy expenditure (p=0.03), exhaustion (p=0.01) and slow gait speed (p=0.03), were shown to be significantly associated with CVD onset, whereas two were not (unintentional weight loss and weakness).34 An independent association was demonstrated between prefrailty and the development of CVD, with low gait speed the best predictor of future CVD. The risk was higher in those meeting two frailty criteria (HR 1.79; 95% CI [1.27–2.52]) rather than one (HR 1.25; 95% CI [1.05–1.64]).34 A limitation in physical functioning alone appears to be associated with a range of important clinical outcomes. Newman et al. used an extended

walking test (400 m) to assess frailty in 3,075 community-dwelling adults, 86% of whom completed the test.29 Compared with the quartile with the fastest walk time (<290 s), the quartile with the slowest walk time (>362 s) had a significantly higher adjusted risk of mortality (HR 3.23; 95% CI [2.11– 4.94]), CVD (HR 1.61; 95% CI [1.05–2.45]), mobility limitation (HR 4.43; 95% CI [3.39–5.78]) and disability (HR 4.43; 95% CI [2.88–6.82]).29 A comparison of gait speed and 6-minute walk distance in 1,474 older people with CVD found that both were associated with all-cause mortality (adjusted HR per 0.1 m/s increase in gait speed 0.87, 95% CI [0.81–0.93], p<0.001; adjusted HR per 10 m increase in 6-minute walk distance 0.96, 95% CI [0.94–0.97], p<0.001).27 In a secondary analysis of longitudinal data, 35 instruments were grouped into four domains, namely Fried phenotype, multidimensional, accumulation of deficits and disability.35 The authors of that study showed that multidimensional frailty scores may have a stronger and more stable association with all-cause mortality and the incidence of cardiovascular events.35 A comparison of a 48-item cumulative deficit index (DI) and a phenotypic frailty index (PFI) showed that death was significantly better predicted by the DI (relative risk [RR] 1.035; 95% CI [1.026–1.045]) than the PFI (RR 1.014; 95% CI [1.009–1.019]) when calculating risks attributable to a 1% increase in the respective index.36 This may be explained by the inclusion of a broader spectrum of disorders and a greater number deficits in the DI than PFI.

Frailty and Acute Coronary Syndrome

The relationship between frailty and the risk of adverse outcome following ST-segment elevation MI (STEMI) and non-STEMI (NSTEMI) has been demonstrated by many studies using different frailty assessment tools (Supplementary Table 2, Table 2 and Table 3). A recent systematic review and meta-analysis evaluated the prognostic value of frailty in 8,554 patients with ACS.37 Frailty was associated with a several-fold increase in the adjusted risk of mortality for patients with STEMI (HR 6.51; 95% CI [2.01–21.10]) and NSTEMI (HR 2.63; 95% CI [1.51–4.60]). A higher risk of mortality was also demonstrated in patients with prefrailty (adjusted HR 1.41; 95% CI [1.19–1.66]). Blanco et al. evaluated the association between frailty and mortality in 236 people aged ≥80 years with ACS (32.2% STEMI, 67.8% NSTEMI).38 The frailest group (EFS >7) comprised 20.8% of the cohort and had the lowest survival rate after a mean follow-up duration of 470 days (38.8% versus 82.4% for the least frail group). Frailty was significantly and independently associated with an increase in the risk of all-cause mortality for the frailest compared with non-frail group (adjusted HR 4.03; 95% CI [2.02–8.04]). Graham et al. also used the EFS for 183 patients with ACS (19.1% STEMI, 80.9% NSTEMI), but in a younger cohort (age ≥65 years).39 In that study, 30.1% of patients had an EFS of ≥7, and these individuals had the highest 1-year mortality (12.7% versus 7.7% and 1.6% for EFS 4–6 and 0–3, respectively). After adjustment for baseline risk differences, the risk of 1-year mortality was 3-5-fold higher for those with an EFS ≥7 than those with an EFS of 0–3 (HR 3.49; 95% CI [1.08–7.61]).39 In another study on patients with ACS (37% STEMI, 41% NSTEMI, 21.9% unstable angina), 48.1% were frail according to the REFS.40 Fewer patients with frailty underwent percutaneous coronary intervention (PCI) than those without frailty (41.7% versus 58.3%; p=0.003). After a 30-day followup, frailty was significantly associated with increased risk of arrhythmias during hospitalisation (adjusted OR 2.24; 95% CI [1.32–3.80]), hospitalacquired pneumonia (adjusted OR 2.27; 95% CI [1.24 4.17]), in-hospital mortality (adjusted OR 3.02; 95% CI [1.35–6.75]), 30-day mortality

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Frailty Scores and CVD (adjusted OR 3.28; 95% CI [1.59–6.76]) and 30-day readmission (adjusted OR 2.53; 95% CI [1.38–4.63]), suggesting that REFS is a useful tool for identifying patients that are at risk of a poor prognosis in the short term. A study of 234 patients with ACS (37.1% STEMI) found that 40.2% of participants were frail according to their SHARE-FI score.15 Frailty was independently associated with a composite of death, non-fatal MI or major bleeding (adjusted HR 2.14; 95% CI [1.13–4.04]) and hospital readmission (adjusted HR 1.80; 95% CI [1.00–3.22]).15 A study using an FI based on claims data in patients with MI found that 19% were frail, and that frailty was associated with 25% greater in-hospital mortality (adjusted OR 1.25; 95% CI [1.22–1.28]).41 Interestingly, although patients with frailty were less likely to receive invasive interventions such as PCI and coronary artery bypass grafting (CABG), their hospital mortality was lower if they had these interventions rather than having none (OR 0.59, 95% CI [0.55– 0.63] for PCI; OR 0.77, 95% CI [0.65–0.93] for CABG). In the TRILOGY ACS trial, frailty was evaluated in 4,996 patients with unstable angina or NSTEMI randomised to clopidogrel or prasugrel.42 The primary endpoint was a composite of cardiovascular death, MI or stroke over 30 months. Frailty was identified in 4.7% of participants using the Fried scale and was independently associated with the primary endpoint (frail versus not-frail: adjusted HR 1.52, 95% CI [1.18–1.98]). There was no significant association between frailty and bleeding (adjusted HR 0.63; 95% CI [0.15–2.58]).42 A study of 7,398,572 patients with ACS (66.8% NSTEMI or unstable angina, 33.2% STEMI) used the HFRS based on ICD-9 codes and divided patients into three frailty groups: low-risk score (LRS), intermediate-risk score (IRS) and high-risk score (HRS).43 In that study, 0.1% of patients were classified as HRS, and these patients had significantly more bleeding complications (OR 2.34; 95% CI [2.03–2.69]), vascular complications (OR 2.08; 95% CI [1.79–2.41]), in-hospital stroke (OR 7.84; 95% CI [6.93–8.86]) and inhospital mortality (OR 2.57; 95% CI [2.18–3.04]) than patients classified as LRS. Patients with HRS were more likely to be managed medically without coronary angiography (31.0%, 54.8% and 70.9% in the LRS, IRS and HRS groups, respectively) and less likely to undergo PCI (42.9%, 21.0% and 14.6% in the LRS, IRS and HRS groups, respectively). Among those who underwent PCI, HRS patients had higher adjusted odds of in-hospital death (OR 9.91; 95% CI [7.17–13.71]), bleeding (OR 4.99; 95% CI [3.82–6.51]) and vascular injury (OR 3.96; 95% CI [3.00–5.23]) than LRS patients.44 Sanchis et al. used the Fried and Green (uses serum albumin, Katz ADL, gait speed and grip strength) scores to assess frailty in patients with ACS (21% STEMI, 79% NSTEMI or unstable angina) at discharge and evaluated postdischarge mortality at a median follow-up of 30 months.45 Frailty when assessed with the Green score demonstrated strongest discriminative accuracy (area under curve [AUC] 0.76) for mortality. A Green score ≥5 was the strongest predictor of mortality (HR 3.4; 95% CI [1.8–6.2]) and death or MI (HR 1.8; 95% CI [1.2–2.8]). Conversely, the Fried score (≥3) was not predictive of mortality (p=0.4) after adjusting for Green score.45 This backs up a recent study, which found sex differences using the Fried score in 488 ACS patients (79.1% NSTEMI).46 A Fried score of ≥3 and the Fried score along its continuum (per 1-point increase) were independently associated with a higher risk of death in the whole sample, but these results were different between men and women. In men, a Fried score of ≥3 was independently associated with all-cause death (HR 1.89; 95% CI [1.25–2.85]), but this relationship was neutral in women (HR 0.92; 95% CI [0.57–1.49]).46 In a comparison study of seven frailty scales for patients admitted for ACS (33% STEMI, 45% NSTEMI, 22% unstable angina), Campo et al. measured

the risk of major adverse cardiovascular and cerebrovascular events (MACCE) and all-cause mortality at 1 year.47 The SPPB, EFS and Fried scales were associated with all-cause mortality, but the SPPB was found to be the best predictor for MACCE (ΔC-statistic: 0.043) and all-cause mortality (ΔC-statistic: 0.063). Using the CFS for 352 patients with ACS (STEMI and NSTEMI), Kang et al. found that frailty was strongly and independently associated with allcause mortality (HR 5.393; 95% CI [1.477–19.692]) and unscheduled return visit (HR 2.832; 95% CI [1.140–7.037]).48 Frail patients were also less likely to undergo coronary angiography (75.66% versus 85.0%; p=0.027). Haemoglobin, albumin and prealbumin concentrations were all significantly lower, whereas high-sensitivity C-reactive protein and interleukin-6 were significantly higher, in frail compared with non-frail patients.48 In another study using CFS (≥5), 11% of the 745 patients with either stable angina or ACS (39.6% STEMI) undergoing PCI were frail.49 In that study, the authors demonstrated a significant association between frailty and increased 30-day mortality (HR 4.8; 95% CI [1.4–16.3]), 1-year mortality (HR 5.9; 95% CI [2.5–13.8]) and longer hospitalisation after PCI. Similar findings were reported by another study on 629 patients who underwent PCI for coronary artery disease (CAD) but in whom frailty was assessed using the Fried scale.50 The association of frailty with mortality or MI at 3 years was significant (HR 2.74; 95% CI [1.12–6.71]) and more prevalent compared with non-frail patients (28% versus 6%). In addition, frailty, comorbidity measured on the Charlson Index and quality of life measured by the 36-Item Short Form Health Survey (SF-36) were associated with adverse long-term outcomes after PCI, and all significantly improved the prognostic ability of the Mayo Clinic risk score.50 Furthermore, using the Fried scale on patients with CAD undergoing PCI (11.9% STEMI, 15.4% NSTEMI) did not reveal any significant differences in 30-day outcomes (death, MI and revascularisation).51 However, the authors of that study demonstrated that the 18.6% of patients who were frail had poorer health status than non-frail patients using the SF-36 and Seattle Angina Questionnaire, and that they had more multivessel or left main CAD than intermediate frail and non-frail patients (74% versus 68% and 60%, respectively; p=0.019).

Frailty and NSTEMI

Table 2 lists studies assessing frailty in patients with NSTEMI. One prospective multicentre observational study of 307 patients with NSTEMI found that 48.5% were frail (CFS 5–7).52 Frailty was strongly and independently associated with in-hospital mortality (OR 4.6; 95% CI [1.3– 16.8]) and 1-month mortality (OR 4.7; 95% CI [1.7–13.0]). At the 5-year follow-up, patients with frailty had significantly higher all-cause mortality than patients without frailty (85.9% versus 53.8% [p<0.001]; adjusted HR 2.06; 95% CI [1.51–2.81]). 53 Similarly, the FRAIL scale was used to screen for frailty in 532 patients aged ≥80 years with NSTEMI.54 Both frailty and prefrailty were associated with 6-month mortality compared with patients without frailty (adjusted HR 2.99, 95% CI [1.20–7.44] for frailty; adjusted HR 2.71, 95% CI [1.09– 6.73] for prefrailty). Coronary angiography was performed in fewer patients with than without frailty, as reported elsewhere.52 The ICON1 study used the Fried criteria to classify 280 patients with NSTEMI from two tertiary centres undergoing invasive treatment strategy, and found 27.5% were frail.55 The primary outcome, which was a composite of MI, need for urgent repeat revascularisation, stroke,

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Frailty Scores and CVD Table 2: Studies Assessing Frailty in Patients with Non-ST-Segment Elevation MI Study

n (% Men)

Age (Years)

Study Cohort and Design Frailty Tool

% Frail

Findings and Outcomes for Frail versus Non-frail

Batty et al.55

280 (60)

≥75

Prospective multicentre cohort Fried scale ≥3 study of patients undergoing invasive management (coronary angiography) for NSTEMI

27.5

1-year mortality: 13% frail versus 2% non-frail (HR 6.93; 95% CI [0.89–54.14]) MI occurrence: 20.3% frail versus 6.1% non-frail (HR 3.18; 95% CI [0.92–11.1]) Repeat all-cause hospitalisation: 34.4% frail versus 20.4% non-frail (HR 2.20; 95% CI [1.07–4.52])

Algre et al.54

532 (61.7)

≥80

Prospective multicentre study of FRAIL scale NSTEMI patients

27.3%

6-month mortality: adjusted HR 2.99; 95% CI [1.20–7.44]; p=0.024 Coronary angiography: 65.5% versus 82.9% (p<0.001)

Ekerstad et al.53 307 (51.1)

Ekerstad et al.52 307 (51.1)

≥75

Prospective multicentre observational study of NSTEMI patients

CSHA CFS (5–7)

Prospective multicentre observational study of NSTEMI patients

CSHA CFS (5–7)

Frail (5–7): 48.5; moderately Long-term all-cause mortality >5 years or severely frail (6–7): 24.1 85.9% frail versus 53.8% non-frail (p<0.001) Mortality from the index hospital admission to the end of follow-up: adjusted HR 2.06; 95% CI [1.51–2.81]; p<0.001 Frail (5–7): 48.5; moderately In-hospital mortality: OR 4.6; 95% CI or severely frail (6–7): 24.1 [1.3–16.8] 1-month mortality: OR 4.7; 95% CI [1.7–13.0]

CFS = Clinical Frailty Scale; CSHA = Canadian Study of Health and Ageing; FRAIL scale = Fatigue, Resistance, Ambulation, Illnesses and Loss of weight scale.

significant bleeding and all-cause mortality at 1 year, occurred in more frail than robust patients (39% versus 18%; HR 2.79; 95% CI [1.28–6.08]). After 1 year, mortality was more common in those with frailty compared with the robust group (13% versus 2%; HR 6.93; 95% CI [0.89–54.14]), as was the occurrence of MI (20.3% versus 6.1%; HR 3.18, 95% CI [0.92–11.1]).

in gait speed: 0.71).59 This shows the variety of frailty tools that can be used to predict worse outcomes in ACS patients and those undergoing invasive interventions. Table 3 summarises studies assessing frailty in patients with STEMI.

Frailty and STEMI

Frailty, as assessed by an FI based on assessment of cognition, mobility, nutrition and instrumental and basic ADL, has shown to be highly predictive of functional decline in older people undergoing transcatheter aortic valve implantation (TAVI).60 Worse outcomes were also demonstrated in the 49% of patients who were identified as frail using a multidimensional geriatric assessment (MGA) consisting of Mini Mental State Examination, mini nutritional assessment, TUG, basic ADL, instrumental ADL and a preclinical mobility disability.61 A higher score on this MGA-based assessment tool was associated with all-cause mortality and MACCE in this cohort, with ORs for 1-year mortality for MGA compared with Society of Thoracic Surgeons score and EuroSCORE of 3.68 (95% CI [1.21–11.19]) and 3.29 (95% CI [1.06–10.15]) on univariate and bivariable analysis, respectively.

Sujino et al. studied early outcomes in 62 patients aged ≥85 years with STEMI (67.7% underwent primary PCI; the rest received conservative therapy).56 According to the CSHA CFS (≥6), 35.5% of patients were frail. Sujino et al. found that higher baseline serum troponin I concentrations (OR 1.02; 95% CI [1.00–1.06]), lower baseline albumin concentrations (OR 0.16: 95% CI [0.02–0.88]) and a CSHA CFS score ≥6 (OR 6.38; 95% CI [1.21–44.7]) were independent predictors of in-hospital mortality. Lower BMI (OR 0.49; 95% CI [0.26–0.76]) and CSHA CFS ≥6 (OR 16.69; 95% CI [2.67–175.02]) were identified as independent predictors of failure of discharge to home.56 An association between severe frailty and mid-term mortality was also observed in STEMI patients undergoing PCI.57 In that study, 3.1% of the 354 patients were frail according to the CFS (≥6), and this was identified as an independent predictor of mid-term all-cause mortality (adjusted HR 2.46; 95% CI [1.52–3.98]), together with higher Killip score (adjusted HR 3.10; 95% CI [1.50–6.39]) and lower serum albumin concentrations (adjusted HR 4.29; 95% CI [2.16–8.51]). Furthermore, Calvo et al. found higher in-hospital mortality for frail STEMI patients undergoing PCI (adjusted OR 3.96; 95% CI [1.16–13.56]).58 In that study, 19.7% of the 259 patients were classified as frail using the FRAIL scale. This predictive model of a simple geriatric assessment showed an optimal ability for predicting in-hospital mortality (AUC 0.83) in patients undergoing PCI. In addition to mortality, cardiovascular events in STEMI patients undergoing PCI can be predicted using gait speed (HR for 0.1 m/s increase

Frailty and Valvular Heart Disease

Similarly, Okoh et al. assessed ADL as well as handgrip strength, gait speed and serum albumin for frailty in patients undergoing TAVI.62 High frailty status, defined as meeting three or four of the criteria, was an independent predictor of increased all-cause mortality (adjusted HR 1.84; 95% CI [1.06–3.17]). In another study on 1,215 patients undergoing TAVI, CFS grade increment was also found to be significantly associated with a 42% higher 30-day mortality (HR 1.42; 95% CI [1.04–1.95]).18 In a study by Green et al., 50% of the 159 patients were frail according to a modified Fried scale.63 Frailty was associated with increased 1-year mortality after TAVI (HR 3.51; 95% CI [1.43–8.62]). Interestingly, gait speed and grip strength, which are both part of the Fried scale, were not associated with survival after TAVI. Instead, ADL status measured with the Katz ADL survey and serum albumin were better than gait speed for identifying frailty-related risk after TAVI.63 These findings are concordant

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Frailty Scores and CVD Table 3: Studies Assessing Frailty in Patients with ST-Elevation MI Study

n (% Men)

Age Study Cohort (Years) and Design

Frailty Tool

% Frail

Findings and Outcomes for Frail Versus Non-frail

Yoshioka et al.57

354 (76.6)

≥27

CSHA CFS (6–7)

3.1

Mortality: CFS 1–3, 21 of 281 (7.5%); CFS 4–5, 13 of 62 (21.0%); and CFS 6–7, 5 of 11 (45.5%) patients (p<0.001)

Retrospective study of STEMI patients who underwent PCI

Independent predictors of mid-term all-cause mortality Higher CFS: adjusted HR 2.46; 95% CI [1.52–3.98]; p<0.001 Higher Killip score: adjusted HR 3.10; 95% CI [1.50–6.39]; p=0.002 Lower serum albumin concentration: adjusted HR 4.29; 95% CI [2.16–8.51]; p<0.001 Calvo et al.58

259 (57.9)

≥75

Observational prospective FRAIL scale study of STEMI patients undergoing PCI

19.7

In hospital mortality: adjusted OR 3.96; 95% CI [1.16–13.56]; p=0.028

Sujino et al.56

62 (58.1)

≥85

Retrospective study of STEMI patients

35.5

Independent predictors of in-hospital mortality: higher baseline serum troponin I level (OR 1.02; 95% CI [1.00–1.06]), lower baseline albumin concentration (OR 0.16; 95% CI [0.02–0.88]) and CSHA CFS score ≥6 (OR 6.38; 95% CI [1.21–44.7])

CSHA CFS ≥6

Independent predictors of failure of discharge to home: lower BMI (OR 0.49; 95% CI [0.26–0.76]) and CSHA CFS ≥6 (OR 16.69; 95% CI [2.67–175.02]) Matsuzawa et al.59 472 (82.2)

63.1 (mean)

Single-centre prospective observational study of STEMI patients undergoing PCI

Gait speeds (200 m course Fastest tertile: 3.2 Gait speed was a significant and independent before discharge), divided Middle tertile: 12.6 predictor of cardiovascular events (HR for 0.1 into three tertiles: slowest Slowest tertile: 36.7 m/s increase in gait speed 0.71; 95% CI [0.63 (n=155), middle (n=159) and to 0.81]; p< 0.001) fastest (n=155)

CFS = Clinical Frailty Scale; CSHA = Canadian Study of Health and Ageing; FRAIL scale = Fatigue, Resistance, Ambulation, Illnesses and Loss of weight scale; PCI = percutaneous coronary intervention.

with a similar study, in which a low Katz Index (<6) was considered to be an independent predictor of long-term all-cause mortality (HR 2.67; 95% CI [1.7–4.3]) after TAVI.64 In a comparative study including the Fried scale and the CFS, the Essential Frailty Toolset (EFT) was most clearly associated with adverse outcomes, including 1-year mortality (adjusted OR 3.72; 95% CI [2.54–5.45]), worsening disability at 1 year (adjusted OR 2.13; 95% CI [1.57–2.87]) and death at 30 days (adjusted OR 3.29; 95% CI [1.73–6.26]) in patients undergoing TAVI (63.3%) or surgical aortic valve replacement (36.7%).65 The EFT is comprised of four items: lower-extremity weakness, cognitive impairment, anaemia, and hypoalbuminaemia. Table 4 summarises the studies assessing frailty in patients with valvular heart diseases.

example, the FI tends to be more commonly used in clinical research datasets, although this has been successfully implemented into routine clinical practice using electronic primary healthcare records.67,68 This has the advantage of enabling the estimation of a ‘baseline’ frailty state, calculated before an acute presentation. However, more accurate assessment is required because the ‘baseline’ frailty state may be independent of the clinical state at the time of hospital admission.

It is increasingly recognised that frailty assessment has the potential to contribute valuable prognostic information in order to inform shared decision making in patients with CVD.9 However, the translation from research to clinical practice remains a challenge, and consensus is lacking on the best tool to use in routine clinical practice.66 This review has summarised the features of frailty instruments used in cardiovascular studies and their utility in clinical practice. It also provides a detailed analysis of outcomes in patients with CVD, with a particular emphasis on coronary and valvular heart diseases.

Frailty is associated with both CVD mortality and non-CVD mortality, which highlights the importance of considering the competing risk of non-CVD mortality when assessing the benefit of CVD interventions in clinical practice.9,69 This is particularly important in a population that is at particular risk of iatrogenic harm. However, the implementation of multidimensional or complex assessment tools, although accurate at predicting mortality in CVD patients, can be challenging in time-dependent situations.35,36,70 Options for frailty assessment in the clinical setting include performance tests that assess the physical functioning of patients. Epidemiological data suggest that slow gait speed is the first domain of the frailty phenotype to manifest rather than weight loss, which tends to occur at a later stage, and the use of gait speed reliably identifies patients at risk of cardiovascular events and mortality.27,29,34,59,71 A decrease in physiological reserve when evaluating physical functioning, or the presence of multisystem deficits, gives useful data on likely recovery after a stressor event, such as ACS or an invasive procedure.60

The most appropriate tool to use is clearly setting dependent, although most frailty scores were developed in the community population. For

The assessment of frailty on the Fried scale and EFS has been adapted in many studies evaluating patients with ACS and has consistently been

Discussion

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Frailty Scores and CVD Table 4: Studies Assessing Frailty in Patients with Valvular Heart Diseases Study

n (% Men)

Age Study Cohort (Years) and Design

Okoh et al.62

75 (35)

>90

Afilalo et al.65

1020 (59)

≥70

Frailty Tool

% Frail

Findings and Outcomes for Frail Versus Non-frail

Prospective cohort study of Modified FI score ≥3/4 patients undergoing TAVI

All-cause mortality after TAVI: adjusted HR 1.84, 95% CI [1.06–3.17]; p=0.028

Prospective multicentre cohort study (FRAILTY-AVR) of patients undergoing TAVI or SAVR

SAVR: Fried 25%, Fried+ EFT was the strongest predictor of death 37%, Rockwood CFS, 12%, at 1 year (adjusted OR 3.72; 95% CI SPPB, 56%, Bern 23%, [2.54–5.45]) Columbia 2%, EFT 17%

Fried scale ≥3, Fried+ (MMSE and mood) ≥3/7, Rockwood CFS ≥5/9, SPPB ≤8/12, Bern ≥3/7, Columbia ≥6/12, EFT ≥3/5

TAVR: Fried 49%, Fried+ 64%, Rockwood CFS 35%, SPPB 74%, Bern 60%, Columbia 59%, EFT 37% Shimura et al.18

Puls et al.64

1215 (29.7)

300 (34)

84.4 (mean)

82.1 (mean)

Prospective multicentre CHSA CFS ≥5 study of patients undergoing TAVI

Observational study of patients undergoing TAVI

EFT was the strongest predictor of worsening disability at 1 year (adjusted OR 2.13; 95% CI [1.57–2.87]) and death at 30 days (adjusted OR 3.29; 95% CI [1.73–6.26])

Mildly frail (CFS 5), 15.1; With increasing CFS grade moderately frail (CFS 6), • Cumulative 1-year mortality: CFS 5 10.0; severely frail (CFS ≥7), 13.4%, CFS 6 17.6%, CFS ≥7 45.1% 4.0 (p<0.001)

Katz Index of ADL (<6)

•

30-day mortality: HR 1.42; 95% CI [1.04–1.95]; p=0.029

•

Late cumulative mortality risk: HR 1.28; 95% CI [1.10–1.49]; p<0.001 per 1-category increase

Immediate procedural mortality: 5.5% versus 1.3% (p=0.04) Procedural mortality: 23% versus 6.4% (p<0.0001) 30-day mortality: 17% versus 5.8% (p=0.002) Long term all-cause mortality: HR 2.67; 95% CI [1.7–4.3]; p<0.0001

Schoenenberger 119 (44.5) et al.60

≥70

Prospective cohort of patients undergoing TAVI

FI ≥3/7

49.6

6-month ADL change ≥1: 31.3% versus 12.1% (OR 3.34, 95% CI [1.18–9.43], p=0.02 for functional decline; OR 4.21, 95% CI [1.72–10.33], p=0.002 for functional decline or death, adjusted for STS) 6-month mortality: 18.6% frail versus 3.3% non-frail

Green et al.63

159 (50)

Stortecky et al.61 100 (40)

≥60

≥70

Prospective cohort of patients undergoing TAVI

Modified Fried scale > median

Prospective cohort study of MGA-based score ≥3/7 elderly high-risk patients with severe aortic stenosis undergoing TAVI

30-day mortality/morbidity: non-significant 1-year mortality: 17% frail versus 7% non-frail (HR= 3.51, 95% CI [1.43–8.62]) 1-year mortality: HR 3.29, 95% CI [1.06–10.15]

ADL = activities of daily living; AVR = aortic valve replacement; CFS = Clinical Frailty Scale; CSHA = Canadian Study of Health and Ageing; EFT = Essential Frailty Toolset; FI = Frailty Index; MGA = multidimensional geriatric assessment; MMSE = Mini Mental State Examination; SAVR = Surgical Aortic Valve Replacement; SPPB = Short Physical Performance Battery; STS = Society of Thoracic Surgeons; TAVI = Transcatheter Aortic Valve Implantation.

associated with mortality.38,39,42,45,47 However, the use of the Fried scale has been questioned in recent studies that found it inferior to other scales or different between sexes, although further analysis is needed to provide a definite answer.45,46 This shows there is no consensus as to which frailty assessment tool to use even though different studies evaluated similar outcomes. In these cases, the use of a well-established tool in the hospital setting may be recommended. However, in studies on patients with NSTEMI or STEMI undergoing PCI, the use of CFS and the FRAIL scale is more commonly seen, suggesting that their use seems more accepted in acute interventional cardiology, although further comparative studies are required to provide a better assessment.54,56–58

The ease and speed with which these assessments can be completed makes their use appealing. If these frailty scales consistently demonstrate reproducibility and efficacy at predicting outcomes, they could be considered as an ideal frailty instrument. There is also a dearth of evidence on the risk of cardiac interventions instead of medical management in patients with frailty. Although invasive interventions are associated with poor outcomes in patients with frailty, this should be weighed against the risk of not intervening, which may result in poorer quality of life with repeated hospitalisation. In these circumstances, frailty assessment for informed decision making requires more clarity.

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Frailty Scores and CVD Figure 1: Multidimensional Assessment of Frailty and Interventions to Reduce Cardiovascular Risk Biological determinants Unintentional weight loss Exhaustion or fatigue Physical activity Walk time or slowness Grip strength or weakness Mobility and balance Comorbidities and deficits Nutrition or appetite Haemoglobin levels Albumin levels Inflammatory biomarkers General health status

Psychological determinants

Cognition Depression Anxiety Coping Memory Frailty

Living alone Social support Social relationships Activities of daily living Functional independence Continence Polypharmacy

May slow down/reverse

Social determinants

Frailty determinants Age Sex Marital status Education level Social circumstances Lifestyle

• Cardiovascular disease onset • Cardiovascular event • Mortality • Mobility limitation • Mobility disability • Less likely to undergo invasive procedures • Complications • Major adverse cardiac and cerebrovascular events • Readmission • Longer hospitalisation • More comorbidities • More likely to be medically managed • Poorer health status

Cardiac rehabilitation Physical exercise Better nutrition/protein-rich diet Lifestyle interventions Cognitive training Medication review

Alternatively, a multidimensional assessment of frailty may be needed. Social frailty was positively associated with physical frailty on the CHS score, whereas the FI and EFS have proved to most accurately predict mortality in comparative studies.72,73 Other frailty subtypes, such as nutritional frailty, may also have a crucial role in predicting outcomes in CVD patients.74,75 Worse quality of life has also been linked to frailty, which supports the importance of multidimensional assessment tools.76 Many studies evaluating frailty in patients undergoing TAVI have included ADL as well as the use of serum biomarkers and assessment of physical frailty.61,62 ADL have even been shown to be better than gait speed at predicting survival in TAVI patients, and may offer potential prognostic aspects in this setting.63 However, the use of ADL or the DAI may not be fully representative of frailty, but partly an element of disability.

Future Directions

Figure 1 summarises the different components present in the assessment of frailty in the different frailty assessment tools discussed in this review. It has been suggested that the progression to frailty may be slowed, which could potentially lead to better outcomes. Suggested interventions in older patients with frailty include increased physical activity, cardiac rehabilitation, 1.

Bergman H, Ferrucci L, Guralnik J, et al. Frailty: an emerging research and clinical paradigm – issues and controversies. J Gerontol A Biol Sci Med Sci 2007;62:731–7. https://doi. org/10.1093/gerona/62.7.731; PMID: 17634320. 2. WHO. Ageing and health. 2018. https://www.who.int/newsroom/fact-sheets/detail/ageing-and-health (accessed 20 May 2020). 3. Afilalo J, Karunananthan S, Eisenberg MJ, et al. Role of frailty in patients with cardiovascular disease. Am J Cardiol 2009;103:1616–21. https://doi.org/10.1016/j. amjcard.2009.01.375; PMID: 19463525. 4. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults:

a protein-rich diet, cognitive training and medication optimisation.77–81 In addition, an exercise intervention has shown promising results in older patients after MI.82 However, evidence is lacking that these measures have a significant effect on overall trajectory, especially in patients with CVD, and further investigation is certainly warranted in this area.

Conclusion

Frailty is common among patients with CVD and is associated with disadvantaged clinical outcomes. Knowledge of a person’s frailty status provides valuable information on prognosis that may be useful in guiding informed shared decision making regarding treatment strategy. The frailty scales discussed are all useful, and personal preference and ease of implementation will play a role as to which one to use. Although the Fried criteria and FI are the most commonly used tools in research, perhaps the use of an easy and quick scale, such as the CFS and FRAIL, or one based on routinely collected data, such as the FI or HFRS, may be more feasible in clinical practice. Currently, however, there is no agreement on the optimal frailty assessment tool, and research into whether decision making based on the routine assessment of frailty improves patient outcomes in cardiology practice is ongoing.

evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146–56. https://doi.org/10.1093/gerona/56.3.M146; PMID: 11253156. 5. Fried LP, Ferrucci L, Darer J, et al. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci 2004;59:255–63. https://doi.org/10.1093/gerona/59.3.M255; PMID: 15031310. 6. Myers V, Drory Y, Gerber Y. Clinical relevance of frailty trajectory post myocardial infarction. Eur J Prev Cardiol 2014;21:758–66. https://doi.org/10.1177/2047487312462828; PMID: 23027593.

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Coronary

Contemporary Management of Isolated Ostial Side Branch Disease: An Evidence-based Approach to Medina 001 Bifurcations Suleiman Suleiman ,1 JJ Coughlan ,2 George Touma3 and Richard Szirt3 1. Department of Cardiology, Tallaght University Hospital, Dublin, Ireland; 2. Deutsches Herzzentrum München, Munich, Germany; 3. St George Hospital, Sydney, NSW, Australia

Abstract

The optimal management of bifurcation lesions has received significant interest in recent years and remains a matter of debate among the interventional cardiology community. Bifurcation lesions are encountered in approximately 21% of percutaneous coronary intervention procedures and are associated with an increased risk of major adverse cardiac events. The Medina classification has been developed in an attempt to standardise the terminology when describing bifurcation lesions. The focus of this article is on the management of the Medina 0,0,1 lesion (‘Medina 001’), an uncommon lesion encountered in <5% of all bifurcations. Technical considerations, management options and interventional techniques relating to the Medina 001 lesion are discussed. In addition, current published data supporting the various proposed interventional treatment strategies are examined in an attempt to delineate an evidence-based approach to this uncommon lesion.

Keywords

Bifurcation lesion, Medina 001, stenting, ostial side branch Disclosure: The authors have no conflicts to declare. Received: 13 October 2020 Accepted: 25 January 2021 Citation: Interventional Cardiology Review 2021;16:e06. DOI: https://doi.org/10.15420/icr.2020.30 Correspondence: Suleiman Suleiman, Department of Cardiology, Tallaght University Hospital, Belgard Square North, Dublin 24, Ireland. E-mail: suleimas@tcd.ie Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The optimal management strategy for percutaneous coronary intervention (PCI) of bifurcation lesions has received significant interest in the scientific literature and remains a matter of debate among the interventional cardiology community. A bifurcation lesion is defined by the European Bifurcation Club as a “coronary artery narrowing occurring adjacent to, and/or involving, the origin of a significant side branch”.1,2 Bifurcation lesions are encountered in approximately 21% of PCI procedures, and they are recognised to confer an increased risk of major adverse cardiac events (MACE).3,4 There is considerable variation in bifurcation lesion anatomy. The Medina classification has been developed in an attempt to standardise the terminology when describing these lesions. In this article, we focus specifically on the management of the Medina 0,0,1 lesion (‘Medina 001’). This is an uncommon lesion that is encountered in <5% of all bifurcations.5 The aim of this paper is to discuss important technical considerations with regard to the treatment of Medina 001 lesions and to describe the current published data supporting the various proposed interventional treatment strategies. In this article, Medina 001 lesions involving the left main stem (LMS) are excluded from the discussion. The rationale for this is because LMS PCI carries its own particular considerations, which are outside the scope of this review.

Laws of Bifurcation Anatomy

Like many other natural phenomena, the coronary arterial tree exhibits ‘fractal geometry’ (i.e. self similarity and scale invariance) as it branches into smaller vessels. Murray’s law states that: “When a parent blood vessel branches into daughter vessels, the cube of the radius of the

parent vessel is equal to the sum of the cubes of the radii of daughter blood vessels.”6 This means that if a branch of radius r splits into two branches with radii r1 and r2, then r3 = r13 + r23. Murray’s law has been used to estimate vessel sizing in coronary bifurcations. Finet et al. have also proposed a simple formula for estimating the diameter of the mother vessel (Dm) and daughter vessels (Dd1, Dd2) based on a simple fractal ratio, and this rule has also been used to estimate vessel sizes: Dm = 0.678 × (Dd1 + Dd2) where Dm is the diameter of the mother vessel and Dd1 and Dd2 are the diameters of the two branching vessels.7

Bifurcation Classifications and Medina 001

The Medina classification describes a bifurcation lesion with three numbers that aim to define the pattern of the atherosclerotic disease based on angiographic appearance.8 Each number is designated either 1 or 0 to indicate the presence or absence of a significant (>50%) stenosis. The first number refers to the proximal main branch (MBprox), the second refers to the distal main branch (MBdistal) and the third refers to the side branch (SB) ostium.8 Lesions that involve both the main branch (MB) and SB are often defined as ‘true bifurcation’ lesions, whereas lesions involving only one of the MB or SB are referred to as ‘non-true bifurcation’ lesions.8 The ‘Medina 001’ indicates isolated ostial SB disease with no disease of the MB. This type of lesion has also been described in the literature as an ‘ostial SB lesion’. There are four other prominent bifurcation classifications described in the literature.9–12 These all share

Contemporary Management of Isolated Ostial Side Branch Disease similar principles, but most of these classifications have failed to make the transition into daily clinical practice.

Defining the Medina 001 Lesion

The initial classification of a bifurcation is often based entirely on angiographic appearance. However, with the use of adjuvant imaging modalities the pattern of bifurcation may be redefined. This is particularly relevant in Medina 001 lesions because the definition of the disease pattern may have important implications with regard to the optimal management approach. Adjuvant modalities that may provide extra information to classify the pattern of disease include quantitative coronary angiography (QCA), intravascular imaging with optical coherence tomography (OCT) or intravascular ultrasound (IVUS) and physiological assessment with fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR). Dedicated QCA software can provide more information than simple angiographic analysis. This includes the three reference diameters (MBprox, MBdistal and SB), lesion length, percentage stenosis and bifurcation angles. However, QCA was initially developed and validated in single, straight coronary segments, and concern remains regarding the accuracy of dedicated bifurcation lesion software and potential inter- and intralaboratory variability. Improvements to available dedicated bifurcation QCA software and novel 3D QCA bifurcation software may help surmount some of these issues and increase the use of these modalities in clinical practice. Intravascular imaging with IVUS or OCT can provide a wealth of information on bifurcation anatomy: it has the ability to accurately measure the true lumen size, vessel diameters, plaque burden and morphology, stent landing zones, stenosis severity and lesion length.13 However, with specific regard to Medina 001 lesions, it should be noted that both OCT and IVUS parameters can have a low positive predictive value for determining the functional significance of SB ostial lesions.14 Physiological assessment of bifurcation anatomy with FFR or iFR can also provide additional ‘functional information’ regarding a lesion that may help guide management. FFR is often considered the gold standard for identifying myocardial ischaemia in the cardiac catheterisation laboratory, and it has been shown to be safe to defer PCI in FFRnegative lesions.15 Götberg et al. demonstrated that among patients undergoing functional determination of an indeterminate coronary stenosis for either stable or unstable coronary disease, iFR was noninferior to FFR in guiding PCI.16 This is particularly relevant for ostial SB lesions, where documentation of negative FFR may obviate the need for PCI. One must be aware of creating a false dichotomy with regard to FFR or iFR positivity, because a positive result does not indicate that PCI must be performed. It is important to note that the benefit observed in the FAME studies was primarily in patients with an FFR value of <0.65.17 As such, it is important to adopt a nuanced approach and recognise that an FFR value of 0.79 or an iFR value of 0.88 is not an absolute indication for PCI. Instead, this may serve as a starting point to consider a patient’s symptom burden, their medication regimen and to incorporate all this information in order to determine the best way to move forward and manage their disease.

Management of Medina 001 Bifurcations

When encountering a Medina 001 lesion in clinical practice, there are several important factors to consider. Prior to performing invasive

intervention, the physician should consider the lesion morphology (with angiographic/intravascular imaging guidance), the presence of ischaemia in the associated territory (non-invasive/invasive documentation) and the clinical scenario (acute coronary syndrome, chronic coronary syndrome, anginal symptom burden). The interventionist must also remain cognisant of the complex interplay between angiographic appearances, symptom burden and documented myocardial ischaemia. Given the risk of MB compromise associated with Medina 001 bifurcation lesions, it is important that the PCI approach is reserved for patients in whom it is truly indicated. With this in mind, there are some pivotal trials that should be considered when discussing the management of Medina 001 lesions. In 2007, the COURAGE trial found no benefit with revascularisation over optimal medical therapy in stable coronary artery disease (CAD).18 The limitations of that study included the randomisation of patients after angiography and the use of bare metal stents. There was also a suggestion that patients with more severe disease would benefit from revascularisation. Subsequently, the ISCHEMIA trial highlighted that, among patients with stable ischaemic heart disease and moderate to severe ischaemia on non-invasive stress testing, a routine invasive strategy failed to reduce major adverse cardiac events compared with optimal medical therapy.19 There was evidence for symptomatic benefit, but it may have been confounded the lack of a blinded sham procedure in the control group. This is important because the ORBITA trial had previously demonstrated that in patients with medically treated angina and a single-vessel, severe coronary stenosis, PCI did not increase exercise time by more than the effect of a sham control procedure.20 Together, these trials remind us of the limitations of PCI with regard to the management of stable CAD. This is particularly relevant when discussing the management of Medina 001 lesions, because the physician must always consider the associated risk of causing MB compromise. When considering this risk–benefit ratio, it is important to remember that Medina 001 lesions will tend to be of lesser prognostic importance that the MB and will supply a relatively small myocardial territory. For example, in a prospective study of 65 patients with left anterior descending (LAD) artery bifurcation lesions, diagonal branch occlusion resulted in lower rates of anginal chest pain (40% versus 100%; p=0.001), ST segment change (37% versus 92%; p=0.001) and arrhythmia compared with occlusion of the LAD.21 Another multicentre registry of 482 patients undergoing coronary CT angiography (CTA) and FFR measurement reported that only one of every five non-left main SBs (n=2,448) supplied a percentage fractional myocardial mass (%FMM) >10% (97% versus 21%; p<0.001).22 Compared with the MB, the SB supplied a smaller myocardial mass and demonstrated less physiological severity despite similar stenosis severity. That study also suggested that an SB supplying a myocardial mass of %FMM ≥10% could be identified by vessel length ≥73 mm (C-statistic=0.85; p<0.001).22 This is a topic of continued debate, but these studies may offer some explanation as to why more aggressive treatment of the SB has failed to show clinical benefit in many coronary bifurcation trials.21,22 Hachamovitch et al. reported that revascularisation compared with optimal medical therapy only had greater survival benefit (absolute and relative) in patients with moderate to large amounts of inducible ischaemia (>10% ischaemia).23 Koo et al. also proposed the SNuH scoring system to estimate the mass of the myocardium at risk when intervening on diagonal SBs.21 The SNuH scoring system takes three factors into account in an

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Contemporary Management of Isolated Ostial Side Branch Disease

MB 3.5 mm

3.5 mm

SB 1.7 mm

° 45

m m

2. 5

Taking these data into account, optimal medical therapy may be a reasonable initial strategy for Medina 001 lesions identified in stable patients, with PCI reserved for patients with refractory anginal symptoms. An observational study of Medina 001 lesions by Brueck et al. lends credence to this approach.24 These authors compared 233 medically managed patients with 69 who were treated with angioplasty for ostial diagonal disease ≥2 mm. PCI resulted in increased rates of rehospitalisation (55% versus 22%; p<0.001) and revascularisation (23% versus 8%; p<0.001) compared with conservative therapy.24 However, these data are non-randomised and so should be interpreted with caution.

Figure 1: Main Branch Protrusion and Ostial Miss in Medina 001 Lesions

45 °

attempt to determine the clinical significance of a diagonal branch: the size of the vessel (vessel diameter ≥2.5 mm=1 point), the number of diagonal branches (number ≤2=1 point) and whether it is the highest branch (no branch below target branch=1 point). However, this scoring system had low positive predictive value, and this highlights the limitations of angiographic assessment in determining the clinical significance of a diagonal SB.21

Bifurcation

Technical Considerations in Treating Medina 001 Lesions

MB protrusion

3.5 mm

The overriding concern when performing PCI for a Medina 001 lesion is the possibility of compromise or injury to the main vessel. This may occur either immediately at the time of intervention or present at a later stage. As the main vessel (by definition) subtends a larger amount of myocardium, a periprocedural myocardial infarction involving the main vessel when the initial aim was to intervene on a smaller SB vessel is a complication that should be avoided at all costs.

1.7 mm

Bifurcation

Ostial miss

It should be recognised that ostial lesions can be fibrotic and calcific, and this may confer a higher risk of stent underexpansion and stent restenosis. Changes in flow and shear stress at the bifurcation likely contribute to this lesion morphology. In continuous segments, flow within the vessel is linear and applies force on the vessel wall, described as wall shear stress (WSS).25,26 Reduced WSS has been associated with the development of atherosclerosis.27 Reduced WSS is commonly seen in coronary bifurcations where flow becomes turbulent, slow and occasionally reversed.25,28 Prior to the level of flow separation, blood flow is brisk and linear. However, in segments opposite the carina in the MB and SB, flow becomes turbulent and oscillatory.25 Histopathological and IVUS analyses have demonstrated that atheroma is frequently located at bifurcations and tends to form in segments with reduced WSS.28,29 Most often, the carina itself is free of atheroma due to these flow dynamics. The pattern of in-stent restenosis can be similarly affected by the same flow mechanics after bifurcation PCI.30 The different flows and shear stresses involved in bifurcation lesions have important implications that may contribute to the increased risk of MACE associated with bifurcation stenting.31,32

A: Projected stent protrusion of 1.7 mm into the main branch while stenting a side branch 2.5 mm in diameter. B: Projected ostial miss of 1.7 mm while stenting a side branch 2.5 mm in diameter. C: Projected minimum combined length of ostial miss and main branch protrusion for three stent sizes at a variety of bifurcation angles. MB = main branch; SB = side branch.

The intertwined concepts of ‘ostial miss’ and ‘MB protrusion’ deserve special mention with regard to Medina 001 lesions. ‘Ostial miss’ refers to the stent being placed too distally and missing the ostium of the SB. ‘MB protrusion’ refers to the stent being placed too proximally and protruding into the MB. This is demonstrated in Figure 1. Operators often speak of landing the stent ‘right at the ostium’ or ‘nailing the ostium’, and various techniques have been described to facilitate achieving this goal. However, as can be seen in Figure 1, with the exception of 90° bifurcation angles, it is not possible from a geometric standpoint to place a stent right at the ostium. For all other angles, there will be at least some degree of ostial miss and/or MB protrusion, however minimal. In Figure 1, we have calculated the

projected minimal combined length of ostial miss and MB protrusion for three stent sizes (2.0, 2.5 and 3.0 mm) implanted in a Medina 001 lesion for a variety of bifurcation angles. This was calculated based on trigonometric analysis of a simplified 2D geometric model of a stent in a Medina 001 lesion, as seen in Figure 1. This combined minimum value remains constant. Reducing the ostial miss length will increase the MB protrusion by the same amount, and vice versa. Interventionists should also note that for bifurcation angles of ≤60°, a minimum combined ostial miss/main vessel protrusion value of >1 mm is inevitable. Both ostial miss and main vessel protrusion may increase the subsequent risk of restenosis in both the main vessel and SB, and therefore should be avoided.

Projected minimum combined ostial miss and main branch protrusion length for various Medina 0,0,1 lesions

Side branch size 2.0 mm

2.5 mm

3.0 mm

Minimal combined ostial miss and main vessel protrusion length (mm)

Bifurcation angle 90°

0 mm

70°

0.68 mm

0.86 mm

1 mm

45°

1.41 mm

1.77 mm

2.1 mm

30°

1.73 mm

2.16 mm

2.59 mm

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Contemporary Management of Isolated Ostial Side Branch Disease Interventional Management

An interventional strategy for the management of Medina 0001 lesions can be divided into techniques that include stenting and those that do not. Lesion preparation is crucial prior to stenting, particularly if the lesions are fibrotic or calcified. If a non-stenting approach is used, the interventionist must be careful not to dissect the vessel and be ready for a bail-out stenting strategy. It is important that this is planned for prior to the PCI and that operators are cognisant that, in some studies, ‘bail-out’ stenting has been associated with an increased risk of mid-term MACE after PCI.33 Operators should always have a Plan B in mind and prepare accordingly. Adjuvant interventional techniques to adequately prepare a Medina 001 lesion may include cutting balloons, scoring balloons, rotational atherectomy and/or intracoronary lithotripsy, as appropriate. Stent underexpansion due to inadequate lesion preparation is a common cause for stent failure.34 These lesions may be technically difficult, and this pattern of calcified and fibrotic disease is often seen in older patients with a greater number of comorbidities, including diabetes, chronic kidney disease and hypertension.35 Deployment of a stent in an unprepared or inadequately prepared lesion may result in stent underexpansion. This should be avoided if possible, because residual stenosis following stent insertion is a major determinant of restenosis after PCI.36

Non-stenting Techniques

Plain Old Balloon Angioplasty

Plain old balloon angioplasty (POBA) was one of the earliest treatment strategies used to treat coronary bifurcation lesions. However, POBA procedures were associated with a low rate of procedural success and frequent complications, such as recoil, dissection and restenosis secondary to intimal disruption.37,38 There has been no dedicated randomised control study on POBA in Medina 001 lesions.

Drug-eluting Balloon Treatment

Drug-eluting balloons (DEB) are semicompliant angioplasty balloons coated with an antiproliferative drug (usually paclitaxel) that is rapidly released upon contact with the vessel wall.39 Stenoses are ideally pretreated with standard balloon angioplasty, a non-compliant balloon and/or scoring or cutting balloons prior to the use of a DEB.40 Once an adequate initial balloon angioplasty result is obtained, the DEB can be inflated for up to 90 s to permit sufficient drug transfer. DEBs have emerged as a potential alternative to drug-eluting stents. One of the benefits associated with the use of a DEB in the management of bifurcation lesions includes homogeneous administration of the drug to the coronary wall, which may negate some of the restenosis seen in comparison with POBA. There may also be less disruption of the carinal anatomy compared with stenting, and the required duration of dual antiplatelet therapy can be reduced. Difficulties encountered with DEBs include issues with antiproliferative drug release, elastic recoil of lesions and coronary dissection. A 3-year multicentre observational registry by Vaquerizo et al. recruited 49 patients with Medina 001 lesions and associated myocardial ischaemia.41 The lesions were prepared carefully using gradually increased inflation pressures in order to reduce the risk of dissection. Once an optimal dilatation result was obtained (defined as a residual stenosis <50%), a Dior paclitaxel DEB (5 mm longer than the predilating balloon) was inflated for >45 seconds. Subsequent bail-out stent implantation was only required in 14% of patients. At 1 year, the rate of target lesion revascularisation was 14%.41 That study showed that DEBs

are a safe and technically feasible therapeutic option for the treatment of Medina 001 lesions. However, as an observational registry, it is hypothesis generating at best, and further dedicated randomised control trials are required to compare DEB to drug-eluting stents in the management of Medina 001 lesions.42–44 From a theoretical standpoint, the DEB has several advantages for Medina 001 lesions. The operator can ensure that the ostium is treated without requiring the implantation of a permanent stent. This removes the previously discussed issue of ostial miss/main vessel protrusion from the equation. At present, DEBs represent a viable option for the treatment of Medina 001 lesions, particularly when SB stenting is not desired. However, randomised data are required to make definitive statements in this regard.

Rotational Atherectomy With or Without Plain Old Balloon Angioplasty

Rotational atherectomy (RA) of the MB has been described in the literature for a wide variety of bifurcation lesions. RA has been postulated to be beneficial in the removal of calcified plaque in front of the SB.45,46 There are limited data regarding the use of RA for ostial SB or Medina 001 lesions. A 26-month prospective observational study reported on the clinical and angiographic outcomes of 105 patients with ostial lesions who underwent RA of SB lesions.47 Supplementary POBA was used if a residual stenosis ≥30% persisted despite appropriate burr sizing or if an angiographic complication developed. Following RA, the mean ± SD percentage diameter stenosis was reduced from 73 ± 13% to 41 ± 14% (p<0.001); adjunct balloon angioplasty was used in 89 procedures (85%), resulting in a 23 ± 14% final diameter stenosis (p<0.001). Procedural success was achieved in 97% of patients.47 Several complications were observed, including minor coronary dissections in 18 patients, coronary spasm in three patients and post-procedural coronary thrombus in three patients. During the 5.4 ± 3.6 months of follow-up, 34% of patients developed recurrent symptoms. Angiographic restenosis was seen in 32% of patients eligible for the 6-month follow-up. Four patients died during follow-up, including three deaths from cardiac causes.47 Although RA has been demonstrated to be an effective tool in other lesion subsets, there remain no randomised data in Medina 001 lesions. Therefore, given the higher complication rates associated with this technique, caution should be advised in the use of RA for Medina 001 lesions at present.

Stenting Strategies

If the decision is made to use a stent, there are several techniques that have been proposed as being particularly suited to Medina 001 lesions. In this section we will describe some of these techniques and, where available, the evidence behind them.

Flush Ostial Technique

The simplest technique is the flush ostial technique. This is colloquially referred to as ‘nailing the ostium’ and involves simply attempting to place the stent exactly at the ostium of the SB. Unfortunately, as discussed above, unless the angle of the bifurcation lesion is at 90° there will inevitably be some degree of ostial miss or MB stent protrusion with this technique, which increases the risk of restenosis of the main vessel and SB.

Stent Draw-back Technique

In the early 2000s, Schwartz and Morsi described the stent draw-back technique.48 In this technique, a stent is located in the SB with a balloon in the main vessel inflated to relatively low pressures. The SB stent is pulled

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Contemporary Management of Isolated Ostial Side Branch Disease Figure 2: Schematic of the Inverted Provisional Stenting Technique of Brunel et al.53

Figure 3: Schematic of the Shoulder Technique of Jim5

back against the inflated balloon until a dent is seen. The stent is then deployed, and the balloon removed thereafter.49 A major disadvantage of this technique is there will inevitably be some degree of injury caused to the main vessel intima due to balloon inflation.

with conventional treatment, the Szabo technique reduced the incidence of stent malposition (6.4% versus 41.0%; p=0.000001) and reduced incomplete scaffolding of the plaque (0.0% versus 7.7%; p=not applicable).52 However, this was based on angiographic analysis rather than intravascular imaging.

An observational series of 100 patients (pull-back = 55, conventional technique = 45) demonstrated a procedural success of 100%.49 The data also suggested that the stent draw-back method was most suited to wide angle bifurcations. As mentioned above, this approach does not overcome the geometrical limitations of minimal combined ostial miss/main vessel protrusion and will only serve to ensure that the combined ostial miss/ main vessel protrusion value is as close as possible to the minimum value.

Szabo Technique

The Szabo technique consists of ‘pushing’ the SB stent over the target vessel wire while a second anchor wire is present in the proximal strut of the stent. The stent is inflated to a low pressure (<4 atm) to allow advancement of the second guide wire. Alternatively, the distal strut may be manually lifted. Following this, the stent is manually recrimped onto the balloon. The stent is delivered over both guide wires and deployed (at 8 atm). The anchor wire is extracted with the stent deployed at high pressure.50 The anchor wire advancing through the proximal stent strut helps prevent excessive protrusion of the stent past the ostium while promoting accurate ostial stenting. It should be emphasised that, again, if the angle is <90°, although the Szabo technique may reduce MB protrusion/ostial miss, it will not eliminate it entirely. The Szabo technique has been demonstrated to be accurate in positioning of the stent due to the protective measures in halting distal advancement. One study achieved almost near perfect successful stent implantation position with IVUS in 40 of 41 patients treated with the Szabo method.51 However, most of these were not Medina 001 lesions. Another retrospective study of a registry compared 78 Medina 010/001 lesions or aorto-ostial lesions treated with the Szabo technique to 179 lesions treated by conventional means.52 The authors reported that compared

Inverted Provisional Stenting/Crossover Technique

The inverted provisional strategy involves placing a stent from the proximal main vessel into the SB. It can be completed as a true provisional technique with only an MB proximal optimisation technique or it can be completed as a provisional technique with kissing balloon inflation and final proximal optimisation, shown in Figure 2.53 The advantage of this technique is that the ostium is completely covered, although this is achieved at the expense of stenting back into the nonsignificantly diseased main vessel. In addition, it is most suitable for situations where there is not a large size mismatch between the two vessels. If there is a significant difference in size between the MB and SB, stent selection requires particular attention to the stent expansion capabilities and limitations. If compromise to the main vessel occurs with this technique, a bail-out two-stent strategy is relatively straightforward via either T and small protrusion (TAP) stenting or a culotte strategy. Brunel et al. reported their experience of inverted provisional T stenting in a registry of 40 patients.53 With this technique, they implanted the stent from the proximal MB through the SB, reopened the struts through the distal MB and finished with a systematic final kissing balloon inflation. Brunel et al. reported complete coverage of the ostial SB in 100% of cases with this technique based on angiographic appearance.53 This allowed the authors to achieve a successful procedure with implantation of a single stent in 92.5% of cases. There were no MACE at 30 days and an acceptable re-intervention rate of 5% at a median follow-up of 22 months.53 Another interesting variation on the inverted provisional technique uses the dedicated Tryton SB stent. Grundeken et al. reported this technique

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Contemporary Management of Isolated Ostial Side Branch Disease Figure 4: Schematic of the Modified Flower Petal Technique of Cayli et al.56

Wire

Stent

Main branch balloon deflated

Stent

Wire

Stent

Wire

Stent

Main branch balloon deflated

using the Tryton Side Branch Stent (Tryton Medical) without a stent in the main vessel.54 Although the authors reported 100% procedural success and only one late clinical adverse event in a small series of 12 patients, there is limited evidence beyond this small series to support this strategy.

Crush Technique Without Main Vessel Stenting

In the crush technique without main vessel stenting, a stent is deployed in the SB with minimal protrusion into the MB. The wire in the SB stent is then removed and a balloon in the MB is used to crush the SB stent flush against the ostium. The SB stent is then rewired and the procedure completed with kissing balloon inflation. This ensures complete SB coverage. Limitations of this strategy include that it requires ballooning in the main vessel. A similar technique was developed in 2014 by Jim et al. (Figure 3).5,55 In this technique, the SB stent is again crushed, but no kissing balloon inflation is performed. Instead, the SB stent is rewired and the lumen of the SB ostium is dilated with high-pressure balloon inflation. Subsequently, a DEB is inflated in the MB. The name of the technique derives from the resultant SB stent appearing like ‘the shoulder of a sleeve’. There are no studies looking at the long-term outcome of the crush technique in Medina 001 lesions.

Modified Flower Petal Technique

Main branch balloon inflated

The modified flower petal technique was proposed by Cayli et al. for Medina 010 and 001 lesions.56,57 A registry of 64 patients was analysed,

Stent

which included both Medina 010 (n=34) and Medina 001 (n=30) lesions. This technique is a modification of flower petal stenting, first described by Kinoshita et al.58 In this modified technique, both branches are initially wired (main vessel and SB). The first wire enters the SB, with the second wire entering the main vessel to act as an anchor (Figure 4).56 Once both branches are wired, a stent balloon system must be prepared outside the guiding catheter. To do this, the plastic stent cover must be pulled back so that the final proximal stent strut is exposed. The stent delivery balloon is inflated to low pressure (5–6 atm) and then deflated. Then, the proximal end of the anchor wire is passed through the final proximal stent strut and another balloon is loaded on the anchor wire as an anchor balloon. The proximal markers of both the stent and balloon are aligned, and the final proximal strut of the stent can then be recrimped by hand. The stent balloon system is now complete. This stent–balloon system can then be passed through the guiding catheter to the target lesion until the anchor balloon halts the continuation of the stent. The concept is that the anchor balloon can avert excessive stent advancement into the target branch. In the technique described by Cayli et al. the stent balloon is firstly inflated and deflated.56,57 The anchor balloon is then inflated and deflated and the stent balloon is the inflated once more. After this, the protruding final proximal strut is in contact with the opposite side of the adjacent vessel wall, the ‘flower petal’ from which the technique derives its name.

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Contemporary Management of Isolated Ostial Side Branch Disease Figure 5: Proposed Treatment Algorithm for Medina 0,0,1 Lesions

The proposed advantage of this technique is the total coverage of the ostial bifurcation lesion with stent struts without encroachment into the main vessel, and a lower metallic burden at the carina segment. At the 9-month follow-up, data were only available for 59 patients.56 There were no cardiac deaths, MIs or stent thrombosis events. Only one patient (1.7%) had binary restenosis on quantitative coronary angiography. Difficulties encountered with this technique included twisting of wires, seen in 10 patients (15.6%).

Medina 0,0,1 lesion

Consider intravascular imaging to clarify anatomy

Conclusion

The Medina 001 lesion is a rarely encountered lesion that presents unique challenges with regard to ostial miss, main vessel protrusion and the potential for main vessel injury and compromise. There is a paucity of highquality, randomised control data to guide the interventional management of Medina 001 lesions.

Confirmed Medina 0,0,1 anatomy? Stable coronary artery disease

Consider patient presentation

ACS?

Most Medina 001 lesions will not supply more than 10% of the myocardium, and so it is important that intervention to these lesions does not compromise the MB. Intravascular imaging and physiological assessment may provide extra information to help guide management and accurately classify the anatomy and functional significance of the bifurcations.

Yes

Consider PCI

Anginal symptoms?

Risks of PCI outweigh benefits

Based on current evidence, medical management should likely retain its position of primacy at present, with PCI reserved for unstable Medina 001 lesions presenting as an acute coronary syndrome or lesions causing refractory angina after a period of medical optimisation.

+/– Medical management of ACS Continue/uptitrate medical management

Evidence of ischaemia in territory supplied by vessel? Yes +/–

Refractory symptoms despite medical optimisation?

FFR+ and symptoms?

Yes

Consider PCI

ACS = acute coronary syndrome; FFR = fractional flow reserve; PCI = percutaneous coronary intervention. 1.

Louvard Y, Medina A. Definitions and classifications of bifurcation lesions and treatment. EuroIntervention 2015;11(Suppl V):V23–6. https://doi.org/10.4244/EIJV11SVA5; PMID: 25983165. Burzotta F, Lassen JF, Lefèvre T, et al. Percutaneous coronary intervention for bifurcation coronary lesions. The 15th consensus document from the European Bifurcation Club. EuroIntervention. 2020. https://doi.org/10.4244/eij-d-2000169; PMID: 33074152; epub ahead of press. Myler RK, Shaw RE, Stertzer SH, et al. Lesion morphology and coronary angioplasty: current experience and analysis. J Am Coll Cardiol 1992;19:1641–52. https://doi. org/10.1016/0735-1097(92)90631-V; PMID 1593061. Renkin J, Wijns W, Hanet C, et al. Angioplasty of coronary bifurcation stenoses: immediate and long-term results of the protecting branch technique. Cathet Cardiovasc Diagn 1991;22:167–73. https://doi.org/10.1002/ccd.1810220303; PMID: 2013078. Jim MH. Shoulder technique: a modified sleeve technique devised for treating isolated coronary stenosis at side branch ostium. Int J Cardiol 2014;171:94–5. https://doi. org/10.1016/j.ijcard.2013.11.076; PMID: 24342408. Murray CD. The physiological principle of minimum work: I. The vascular system and the cost of blood volume. Proc Natl

8. 9.

10.

11.

If stenting must be performed, operators must accept that, with the exception of 90° bifurcation angles, some degree of ostial miss or MB stent protrusion is inevitable, regardless of the strategy used, which may result in poor outcomes to either the main vessel, SB or both. With this in mind, the authors feel the most appropriate stenting strategy is the inverted provisional/crossover technique, which ensures complete ostial coverage. This technique is also relatively safe if compromise to the main vessel occurs, because placement of a second stent is reasonably straightforward. DEB treatment, with or without cutting balloon lesion preparation, has some theoretical advantages over stenting for Medina 001 PCI. However, randomised control data to support this are lacking at present, and this is an area for future research. In Figure 5, we present a proposed management algorithm for Medina 001 lesions.

Acad Sci USA 1926;12:207–14. https://doi.org/10.1073/ pnas.12.3.207; PMID: 16576980. Finet G, Gilard M, Perrenot B, et al. Fractal geometry of arterial coronary bifurcations: a quantitative coronary angiography and intravascular ultrasound analysis. EuroIntervention 2008;3:490–8. https://doi.org/10.4244/ EIJV3I4A87; PMID: 19736093. Medina A, Suárez de Lezo J, Pan M. A new classification of coronary bifurcation lesions. Rev Esp Cardiol (Engl Ed) 2006;59:183. https://doi.org/10.1016/S1885-5857(06)60130-8. Lefèvre T, Louvard Y, Morice MC, et al. Stenting of bifurcation lesions: classification, treatments, and results. Catheter Cardiovasc Interv 2000;49:274–83. https://doi. org/10.1002/(SICI)1522-726X(200003)49:3<274::AIDCCD11>3.0.CO;2-N; PMID: 10700058. Lefèvre T, Ormiston J, Guagliumi G, et al. The Frontier stent registry: safety and feasibility of a novel dedicated stent for the treatment of bifurcation coronary artery lesions. J Am Coll Cardiol 2005;46:592–8. https://doi.org/10.1016/j. jacc.2005.05.033; PMID: 16098421. Todaro D, Burzotta F, Trani C, et al. Evaluation of a strategy for treating bifurcated lesions by single or double stenting based on the Medina classification. Rev Esp Cardiol 2009;62:606–14. https://doi.org/10.1016/s1885-

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5857(09)72224-8; PMID: 19480756. 12. Movahed MR, Kern K, Thai H, et al. Coronary artery bifurcation lesions: a review and update on classification and interventional techniques. Cardiovasc Revasc Med 2008;9:263–8. https://doi.org/10.1016/j.carrev.2008.05.003; PMID: 18928952. 13. Legutko J, Yamawaki M, Costa RA, Costa MA. IVUS in bifurcation stenting: what have we learned? EuroIntervention 2015;11(Suppl V):V55–8. https://doi.org/10.4244/EIJV11SVA12; PMID: 25983172. 14. Koh JS, Koo BK, Kim JH, et al. Relationship between fractional flow reserve and angiographic and intravascular ultrasound parameters in ostial lesions: major epicardial vessel versus side branch ostial lesions. JACC Cardiovasc Interv 2012;5:409–15. https://doi.org/10.1016/j. jcin.2012.01.013; PMID: 22516397. 15. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49:2105–11. https://doi. org/10.1016/j.jacc.2007.01.087; PMID: 17531660. 16. Götberg M, Christiansen EH, Gudmundsdottir IJ, et al. Instantaneous wave-free ratio versus fractional flow reserve to guide PCI. N Engl J Med 2017;376:1813–23.

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30. Nakazawa G, Yazdani SK, Finn AV, et al. Pathological findings at bifurcation lesions: the impact of flow distribution on atherosclerosis and arterial healing after stent implantation. J Am Coll Cardiol 2010;55:1679–87. https://doi. org/10.1016/j.jacc.2010.01.021; PMID: 20394871. 31. van der Giessen AG, Wentzel JJ, Meijboom WB, et al. Plaque and shear stress distribution in human coronary bifurcations: a multislice computed tomography study. EuroIntervention 2009;4:654–61. https://doi.org/10.4244/EIJV4I5A109; PMID: 19378688. 32. Medina A, Martín P, Suárez de Lezo J, et al. Ultrasound study of the prevalence of plaque at the carina in lesions that affect the coronary bifurcation. Implications for treatment with provisional stent. Rev Esp Cardiol (Engl Ed) 2011;64:43–50. https://doi.org/10.1016/j.rec.2010.06.008; PMID: 21190777. 33. Zimarino M, Briguori C, Amat-Santos IJ, et al. Mid-term outcomes after percutaneous interventions in coronary bifurcations. Int J Cardiol 2019;283:78–83. https://doi. org/10.1016/j.ijcard.2018.11.139; PMID: 30528620. 34. Virmani R, Farb A, Burke AP. Coronary angioplasty from the perspective of atherosclerotic plaque: morphologic predictors of immediate success and restenosis. Am Heart J 1994;127:163–79. https://doi.org/10.1016/00028703(94)90522-3; PMID: 8273736. 35. Akin I, Pohlmann S, Nienaber CA, Ince H. A different way of coronary lesion preparation: stentablation and rotastenting. Clin Med Insights Cardiol 2012;6:53–6. https://doi.org/10.4137/ CMC.S8959; PMID: 22408370. 36. Cheneau E, Leborgne L, Mintz GS, et al. Predictors of subacute stent thrombosis: results of a systematic intravascular ultrasound study. Circulation 2003;108:43–7. https://doi.org/10.1161/01.CIR.0000078636.71728.40; PMID: 12821553. 37. Zack PM, Ischinger T. Experience with a technique for coronary angioplasty of bifurcational lesions. Cathet Cardiovasc Diagn 1984;10:433–43. https://doi.org/10.1002/ ccd.1810100504; PMID: 6240319. 38. Meier B, Gruentzig AR, King SB, et al. Risk of side branch occlusion during coronary angioplasty. Am J Cardiol 1984;53:10–4. https://doi.org/10.1016/0002-9149(84)90675-1; PMID: 6229173. 39. Jackson D, Tong D, Layland J. A review of the coronary applications of the drug coated balloon. Int J Cardiol 2017;226:77–86. https://doi.org/10.1016/j.ijcard.2016.09.045; PMID: 27792992. 40. Durante A, Laforgia PL. Drug-coated balloons and coronary bifurcation lesions. EMJ Int Cardiol 2017;5:80–4. 41. Vaquerizo B, Fernández-Nofreiras E, Oategui I, et al. Second-generation drug-eluting balloon for ostial side branch lesions (001-bifurcations): mid-term clinical and angiographic results. J Interv Cardiol 2016;29:285–92. https://doi.org/10.1111/joic.12292; PMID: 27245124. 42. Kleber FX, Rittger H, Ludwig J, et al. Drug eluting balloons as stand alone procedure for coronary bifurcational lesions: results of the randomized multicenter PEPCAD-BIF trial. Clin Res Cardiol 2016;105:613–21. https://doi.org/10.1007/s00392015-0957-6; PMID: 26768146. 43. Berland J, Lefèvre T, Brenot P, et al. Danubio – a new drugeluting balloon for the treatment of side branches in bifurcation lesions: six-month angiographic follow-up results of the DEBSIDE trial. EuroIntervention 2015;11:868–76. https:// doi.org/10.4244/EIJV11I8A177; PMID: 26696455. 44. Jim MH, Lee MK, Fung RC, et al. Six month angiographic result of supplementary paclitaxel-eluting balloon deployment to treat side branch ostium narrowing

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Structural

Transcatheter Mitral Valve Replacement: Current Evidence and Concepts Ozan M Demir ,1 Mhairi Bolland,2 Jonathan Curio ,3 Lars Søndergaard ,4 Josep Rodés-Cabau ,5 Simon Redwood ,1 Bernard Prendergast ,1 Antonio Colombo ,6 Mei Chau7 and Azeem Latib 8 1. Department of Cardiology, St Thomas’ Hospital, London, UK; 2. Department of Cardiology, Imperial College Healthcare NHS Trust, London, UK; 3. Department of Cardiology, Charité University Medical Care, Campus Benjamin Franklin, Berlin, Germany; 4. Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 5. Quebec Heart and Lung Institute, Laval University, Quebec City, Canada; 6. Interventional Cardiology Unit, GVM Care and Research, Maria Cecilia Hospital, Cotignola, Italy; 7. Department of Cardiac Surgery, Montefiore Medical Center, New York, US; 8. Department of Cardiology, Montefiore Medical Center, New York, US

Abstract

Over the past decade, several transcatheter devices have been developed to address the treatment of severe mitral regurgitation (MR) in patients at high surgical risk, mainly aimed at repairing the native mitral valve (MV). MV repair devices have recently been shown to have high efficacy and safety. However, to replicate promising trial results, specific anatomical and pathophysiological criteria have to be met and operators need a high level of experience. As yet, the longer-term durability of transcatheter MV repair remains unknown. Transcatheter MV replacement (TMVR) might be a treatment option able to target various anatomies, reliably abolish MR, and foster ease of use with a standardised implantation protocol. This review presents upcoming TMVR devices and available data and discusses how TMVR might further advance the field of transcatheter treatment of MR.

Keywords

Mitral regurgitation, transcatheter mitral valve replacement, transcatheter mitral valve repair, percutaneous mitral valve replacement, heart failure Disclosure: JRC receives institutional research grants from and is a consultant for Edwards Lifesciences, Medtronic and Abbott. AL is a consultant for Edwards Lifesciences, Medtronic and Abbott. All other authors have no conflicts of interest to declare. Received: 21 August 2020 Accepted: 4 January 2021 Citation: Interventional Cardiology Review 2021;16:e07. DOI: https://doi.org/10.15420/icr.2020.25 Correspondence: Azeem Latib, Department of Cardiology, Montefiore Medical Center, 111 East 210th St, Bronx, New York 10467–2401, US. E: alatib@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Mitral regurgitation (MR) is the most prevalent form of valvular heart disease in the developed world, affecting about 10% of people aged over 75 years.1–3 MR can be categorised as primary MR when it occurs as a result of pathological changes in the mitral valve (MV) apparatus and secondary MR when it occurs as a result of ventricular or atrial remodelling due to chronic volume overload leading to functional impairment with a structurally normal MV apparatus.4 The management of MR is dependent on numerous factors, including the aetiology, pathophysiology, natural history and expected efficacy of treatment. While the gold standard treatment of MR is MV repair or replacement, up to 50% of patients with severe symptomatic MR are not referred for surgery.5 Mortality rates for patients with severe symptomatic MR approach 50% at 5 years and the vast majority (90%) have at least one hospitalisation following diagnosis.6 Reasons for the low rates of surgical referral are multifactorial but principally relate to the presence of concomitant cardiac and non-cardiac comorbidities. Therefore, an unmet clinical need remains for the large subset of patients who have high risk of morbidity and mortality. Transcatheter MV replacement (TMVR) is a potential therapeutic option. Over the past decade, several transcatheter MV repair devices have been used for patients who have a high or prohibitive surgical risk. These approaches have been derived from numerous surgical techniques. Transcatheter MV repair is most commonly performed using either the

MitraClip (Abbott Vascular) device or the PASCAL system (Edwards Lifesciences). However, several other transcatheter MR repair approaches are in development or already undergoing clinical testing. The MitraClip and the PASCAL device mimic surgical edge-to-edge leaflet repair with the MitraClip being used in more than 100,000 procedures since its introduction in 2003 with high success and safety rates.7 Recently, the COAPT trial demonstrated that intervention with MitraClip in patients with moderate-to-severe or severe secondary MR and impaired left ventricular function resulted in lower all-cause mortality and lower rates of hospitalisation for heart failure compared with medical therapy alone at 24 months follow-up.8 On the other hand, the MITRA-FR trial did not demonstrate a benefit of transcatheter intervention compared with medical therapy.9 While several differences between these two trials have been discussed, including potentially lower operator experience and suboptimal optimisation of medical therapy in the MITRA-FR trial, the most widely referenced explanation for the disparate outcomes is the concept of disproportionately severe MR in combination with a more preserved left ventricle in the COAPT trial, hence leading to greater interventional efficacy.10 However, it is important to note that outcome data for the MitraClip is primarily based on treatment in patients with secondary MR.

Transcatheter Mitral Valve Replacement: Concepts and Evidence TMVR is an alternative to transcatheter MV repair and offers several potential advantages. First, the pathophysiology of MV disease is complex, resulting in a heterogeneous anatomical spectrum that may be difficult to treat with current transcatheter MV repair devices. A TMVR device able to negate this heterogenicity and target numerous anatomical variations would therefore be a tangible advantage. TMVR would result in a standardised universal treatment for the treatment of MV disease, and it would result in more predictable reduction in MR than MV repair while remaining less invasive than current surgical techniques.11

for surgery. Secondary outcomes include performance, adverse events and clinical outcomes at 1 year.20 The TIARA-II study (NCT03039855) is an ongoing international, multicentre, single-arm, prospective study that aims to enrol 115 participants with an estimated completion date in January 2026. More than 50 patients have been treated with the TIARA TMVR with 95% implant success, no intraoperative mortality and 8.5% 30-day mortality.20 Given the valve design and mode of implantation, it will be challenging to implement the current design via transseptal approach.

Early experiences with TMVR have demonstrated that it is a feasible treatment option in patients who are at high or extreme risk for conventional MV surgery.12–16 In this review we provide a comprehensive overview of the feasibility and early clinical trial outcomes of TMVR devices that are currently under evaluation.

Tendyne Transcatheter Mitral Valve

TMVR Devices EVOQUE Transcatheter Mitral Valve

The EVOQUE transcatheter mitral valve (Edwards Lifesciences) is a selfexpanding bovine tissue trileaflet prosthesis with a nitinol frame and polyester fabric skirt and a symmetric design that does not require rotational alignment to the mitral annulus.17 The frame features two sets of opposing anchors that secure and align the device with the native mitral annulus. The polyurethane foam-covered left ventricular anchors are designed to engage and preserve the subvalvular MV apparatus.17 The device can be delivered either via transfemoral/transseptal or transapical route using a 33 Fr delivery system.17 Numerous reports described early human experience with the CardiAQ valve (later reiterated to become the EVOQUE valve) following the first in-human implantation in 2012.18 Unfortunately, the RELIEF trial (NCT02722551) that aimed to evaluate the earlier CardiAQ valve was terminated prematurely due to safety concerns before recruiting any patients. Further design improvements resulted in the iterated EVOQUE valve with its own dedicated trial. The open-label single-arm transfemoral EVOQUE study (NCT02718001) is ongoing and aims to enrol 58 patients with a primary completion date of December 2024 (Table 1). The primary outcome measure is device and procedural safety and the secondary outcomes are New York Heart Association (NYHA) functional class, 6-minute walk test and reduction in MR grade.

Tiara Transcatheter Mitral Valve

The Tiara TMVR prosthesis (Neovasc) has a self-expanding nitinol alloybased frame with a trileaflet bovine pericardial valve and can be delivered via a 32 Fr delivery system.19 The valve is D-shaped to geometrically fit the native MV annulus and the device is fixated radially by expansion of the Tiara valve and axially by the ventricular tabs (two anterior and one posterior).20 The ventricular tabs are designed to secure the valve (two attached to the anterior fibrous trigones and one anchoring the valve posteriorly to the shelf of the mitral annulus) thereby preventing migration and minimising the risk of paravalvular leakage, left ventricular outflow tract (LVOT) obstruction and coronary ostial encroachment.20 The Tiara TMVR has two sizes (35 mm: internal dimensions 30 × 35 mm, area 6.3–9 cm2; 40 mm: internal dimensions 34.2 × 40 mm, area 9–12 cm2) and is implanted via transapical approach.19 The first in-human implantation was performed in Canada in January 2014.19 The TIARA-I study (NCT02276547) is an ongoing international, multicentre, single-arm, prospective study of 30 patients, primarily examining 30-day safety outcomes in patients with severe MR at high risk

The Tendyne TMVR prosthesis (Abbott Vascular) is a fully repositionable and retrievable, double-frame designed device composed of a trileaflet porcine pericardial valve with an effective orifice area >3.2 cm2 mounted on a self-expanding nitinol frame and in January 2020 became the first TMVR device to receive CE mark approval.21 The inner circular frame of the prosthesis is of fixed size and supports the leaflets. The size of the outer (sealing) frame ranges from 30–43 mm in the septal-lateral dimension and 34–50 mm in the intercommissural dimension. The D-shaped prosthesis conforms to the shape of the MV apparatus with the straight edge resting on the atrial wall.21 It has a porcine pericardial covering and a polyethylene terephthalate cuff to assist mitral annular sealing. Anteriorly, the cuff of the outer frame extends above the annular plane, abutting the anterior atrial wall and aorto-mitral continuity.16 The device is one of the few TMVR devices to be completely repositionable and retrievable and it is delivered via a 34 Fr transapical sheath accessed via a small left anterior thoracotomy with a left ventricular apical tethering system and apical pad that anchors the device and assists with apical closure.21,22 The tension on the tether can be adjusted during the procedure to minimise paravalvular leak or LVOT obstruction.21 The first in-human implantation of the Tendyne prosthesis was in February 2013 and outcomes were reported the following year as part of a twopatient series demonstrating dramatic improvement in intracardiac pressures and grade of MR. Devices were then explanted and the patients proceeded to conventional valve replacement surgery as per the study protocol.23 The Tendyne Global Feasibility Trial (NCT02321514) is the largest published evaluation of this device and it looked at outcomes at 30 days and 1 year following TMVR with the Tendyne prosthesis via transapical delivery in a prospective non-randomised fashion.24 The trial enrolled 100 patients (mean age 75.4 ± 8.1 years, secondary MR n=89, primary MR n=11) at 24 study sites between November 2014 and November 2017. Successful device implantation was achieved in 96 patients (96%), with no intraprocedural deaths, two (2%) disabling strokes and two (2%) MIs during the hospital stay. Mortality was 6% at 30 days and 26% at 1 year, with no MR in 98.4%, mean mitral gradient 3.0 ± 1.1 mmHg and no LVOT obstruction. Among survivors, 88.5% were in NYHA class I/II, with bleeding events and need for reintervention in 8% and 4%, respectively, at a mean follow-up of 13.7 months. Device-associated thrombus was observed in 6%, but no further thrombi were detected after a protocol change requiring post-procedural warfarin (target international normalized ratio 2.5–3.5) for over 3 months.24 The study is still expanding to gain further data on the safety and performance of the Tendyne device with the aim to include 350 participants across 40 centres over a 5-year period post implantation with an estimated study completion date of December 2025.

INTERVENTIONAL CARDIOLOGY REVIEW Access at: www.ICRjournal.com

Transcatheter Mitral Valve Replacement: Concepts and Evidence Table 1: Summary of Transcatheter Mitral Valve Replacement Studies Transcatheter Trial Name Mitral Valve Replacement System

Study Type

Inclusion Criteria

Outcomes

Estimated Primary Completion Date

EVOQUE

EVOQUE (NCT02718001)

Single-arm, open-label

Clinically significant, symptomatic MR, high risk for open-heart surgery, specific anatomical criteria

Safety assessed by freedom from device or procedurerelated adverse events at 30 days

December 2024

TIARA

TIARA-I (NCT02276547)

Single-arm, open-label

Severe symptomatic MR (stage D), 30 high surgical risk for open MV surgery, specific anatomical criteria for available size(s), NYHA class III/IV

Freedom from all-cause mortality and major adverse events, stroke, MI, renal failure requiring dialysis, lifethreatening bleeding, and cardiac surgical or transcatheter reintervention at 30 days

December 2019 (realised)

TIARA-II (NCT03039855)

Single-arm, open-label

Severe MR, high surgical risk for open MV surgery, specific anatomical criteria

Freedom from all-cause mortality, MAE and reduction of MR to optimal or acceptable at 30 days

January 2021

Tendyne

115

Feasibility Study of the Single-arm, Tendyne Mitral Valve System open-label for Use in Subjects with Mitral Annular Calcification (NCT03539458)

Not suitable for conventional 11 surgical treatment due to degree of mitral annular calcification and likely to benefit from transcatheter valve implantation. Severe symptomatic MR, NYHA ≥ II (if class IV, patient must be ambulatory), age ≥18 years, not a member of a vulnerable population

Device success and freedom from device and procedure related serious adverse events (MVARC criteria) at 30 days

October 2019 (realised)

SUMMIT (NCT03433274)

Randomised, parallel assignment, open-label

Symptomatic, severe MR, NYHA ≥ II (must be ambulatory if class IV), local heart team determines that subject has been adequately treated per applicable standards, not a member of a vulnerable population

958

Mortality and HF hospitalisation at 12 months (randomised and MAC cohort); composite of mortality, HF hospitalisation, stroke, reintervention (non-randomised cohort)

June 2022

Expanded Clinical Study of the Tendyne Mitral Valve System (NCT02321514)

Single-arm, open-label

Severe MR of primary and secondary aetiology, NYHA class ≥ II (must be ambulatory if class IV), heart team determines unsuitable for traditional surgical treatment, age ≥18 years

350

Safety assessed by freedom from device or procedure related adverse events at 30 days

July 2020 (realised)

1600

Preliminary results for 100 patients published

Performance assessed by freedom from device malfunction at 30 days

Intrepid

APOLLO (NCT03242642)

Randomised, parallel assignment, open-label

Moderate/severe or severe symptomatic MR, candidate for bioprosthetic MV replacement as determined by heart team

HighLife

HighLife Transcatheter Mitral Valve Replacement System Study (NCT02974881)

Single group assignment, open-label

Age ≥18 years, severe MR, NYHA 5 II, III or ambulatory IV, patient receiving maximally tolerated GDMT (including CRT) for at least 3 months, MDT consensus that patient is inoperable or at high risk for surgical repair/replacement, MDT consensus patient is unsuitable for other approved percutaneous repair therapy, patient meets anatomical criteria for HighLife valve sizing as determined by CT and TOE

All-cause mortality, stroke, reoperation (or reintervention) and cardiovascular hospitalisation at 1 year (randomised and single-arm cohort), all-cause mortality and HF hospitalisation (MAC cohort)

October 2021

Freedom from MAEs at 30 days

November 2018 (realised)

Continued intended performance of bioprosthesis at 30 days Technical success immediately after the procedure

(Continued) INTERVENTIONAL CARDIOLOGY REVIEW Access at: www.ICRjournal.com

Transcatheter Mitral Valve Replacement: Concepts and Evidence Table 1 (cont.): Transcatheter Trial Name Mitral Valve Replacement System

Study Type

Inclusion Criteria

Outcomes

Estimated Primary Completion Date

Cardiovalve

AHEAD EU (NCT03339115)

Single group assignment, open-label

Age ≥18 years, NYHA II, III or ambulatory IV, severe MR (MR grade 3–4+), subject on optimal GDMT for heart failure for at least 30 days (and CRT if indicated), heart team adjudication of elevated risk for conventional open replacement or repair surgery, able to undergo TOE

Freedom from all-cause mortality and MAEs at 30 days, 3 months, 6 months, 12 months and 24 months

December 2020

AHEAD (NCT03813524)

Single group assignment, open-label

Age 18–85 years, symptomatic severe MR (stage D) confirmed by echo, cardiac index >2.0, LVEF ≥30%, NYHA class II, III or ambulatory IVa, prior treatment with GDMT for HF for at least 30 days, heart team adjudication of high surgical risk (MVARC definition)

Cardiovalve technical success without procedural mortality, stroke or device dysfunction at 30 days

April 2022

Major device-related adverse event at 30 days

AltaValve

AltaValve Early Feasibility Study (NCT03997305)

Single group assignment, open-label

Age ≥18 years, NYHA II–IV, severe 15 MR as documented by echo, subjects at high risk for open-heart surgery as documented by the health care professional (e.g., MDT of cardiac surgeon and interventional cardiologist in the US)

MAEs at 30 days, technical success per MVARC criteria at procedure completion, device success per MVARC criteria and change in MR grade at 30 days

December 2022

Cephea

Cephea Transseptal Mitral Valve System FIH (NCT03988946)

Single group, open-label

MR 3+ or 4+, NYHA II, III or ambulatory IV, LVEF >30%, poor candidate for surgery

Safety: free from MAE at 30 days

December 31, 2019 (realised)

ENCIRCLE trial (NCT04153292)

Single group assignment, open-label

Age ≥18 years, MR ≥3+, NYHA class ≥II, per the heart team commercially available surgical or transcatheter options deemed unsuitable, GDMT optimised and stable for at least 30 days

400

Sapien M3

Performance: MR ≤1+ at 30 days Composite of death and heart failure rehospitalisation at 1 year, improvement in NYHA, KCCQ scores and MR compared with baseline at 1 year

February 2024

CRT = cardiac resynchronisation therapy; FIH = first in-human; GDMT = guideline directed medical therapy; HF = heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricular ejection fraction; MAC = mitral annular calcification; MAE = major adverse events; MDT = multidisciplinary team; MR = mitral regurgitation; MV = mitral valve; MVARC = mitral valve academic research consortium; NYHA = New York Heart Association; TOE = trans-oesophageal echocardiogram; TMVR = transcatheter mitral valve replacement.

The SUMMIT trial (NCT03433274) is a prospective, multicentre clinical trial consisting of three arms: a randomised cohort (Tendyne versus MitraClip, 1:1 ratio), a non-randomised cohort treated with Tendyne and a mitral annular calcification cohort treated with Tendyne. The trial aims to enrol 958 patients with 1-year follow-up and completion is estimated in June 2026.

Intrepid Transcatheter Mitral Valve

The Intrepid TMVR system (Medtronic) consists of a circular trileaflet selfexpanding bovine pericardial valve contained within a nitinol frame. It has a unique dual structure design, consisting of an inner stent with valve attached and an independent conformable outer fixation ring to engage mitral annular anatomy, accommodate the dynamic variability of the MV and mitral annulus and prevent disruption of the shape of the inner frame throughout the cardiac cycle.25 A flexible brim is attached to the atrial end of the fixation ring to facilitate imaging with ultrasound during implantation.13 The Intrepid TMVR system is built around a 27 mm inner valve structure with an effective orifice area (EOA) of 2.4 cm2 and outer diameters of 43 mm, 46 mm and 50 mm. Delivery is via transapical access guided by transoesophageal echocardiography (TOE) and fluoroscopy, and first implantations were undertaken in 2014.26

The APOLLO trial (NCT03242642) involving an estimated 1,600 patients started in 2017 and has two arms – one randomising TMVR versus traditional surgery in patients with severe, symptomatic MR and the second enrolling a single cohort of patients treated with TMVR who are ineligible for surgery. The primary endpoint is a composite of all-cause mortality, stroke, reoperation (or reintervention) and cardiovascular hospitalisation at 1 year with anticipated primary completion in 2021.

HighLife Transcatheter Mitral Valve

The HighLife device (HighLife SAS) is composed of two components – a subannular ring that is positioned around the native leaflets and a prosthetic TMVR that is positioned within. The sub-annular implant consists of a polymer tube with nitinol hooks for ring closure that is placed around the prosthesis to avoid displacement into the left ventricle and LVOT obstruction. Once in its final position, the native leaflets are trapped between the sub-annular implant and the prosthetic valve. The HighLife prosthesis is composed of a 31 mm nitinol frame and a trileaflet bovine pericardial valve with a pre-formed annular groove. Both the valve and ring are covered with Dacron and are completely endothelialised after a few months, embedding them to local structures and increasing stability.27

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Transcatheter Mitral Valve Replacement: Concepts and Evidence The prosthesis is available in one size and is delivered via transfemoral venous access and transseptal puncture, while the ring is delivered via transfemoral arterial approach.27,28 Initial results from a single centre feasibility study enrolling six patients treated with the HighLife TMVR were recently presented. Technical success was achieved in 83.3% (n=5) with one patient requiring conversion to open-heart surgery. There was one procedural mortality and a further mortality at 30-day follow-up, but no moderate or severe MR in the remaining four survivors.29 The HighLife Transcatheter Mitral Valve Replacement System study (NCT02974881) is a multicentre clinical study evaluating the feasibility, safety and performance of the HighLife TMVR system in patients with severe symptomatic MR who are unsuitable for surgical intervention and have heart team approval for percutaneous treatment. All patients will be followed up over 12 months with long-term performance and safety assessed annually up to 5 years after the intervention. Study completion is anticipated in December 2023.

Cardiovalve Transcatheter Mitral Valve

The Cardiovalve TMVR system (Cardiovalve) is a self-expandable trileaflet valve available in three sizes (range 40–50 mm) for delivery via transfemoral approach. It has a symmetrical design that is anchored into the mitral annulus by 24 atraumatic grasping legs. It has a low ventricular profile and protrudes into the left ventricle by only 12 mm after deployment. The Cardiovalve TMVR system has been successfully implanted into five patients with normal haemodynamic outcomes, no LVOT obstruction, no MR and either trace (n=3) or no paravalvular leak (n=2). Although three of the five patients died at 30 days due to issues with bleeding or vascular access, the surviving two have demonstrated promising outcomes, including sustained elimination of MR without further complications at 1 year.30 The AHEAD EU (NCT03339115) is a multi-centre, prospective, single-arm pilot clinical study enrolling a total of 30 subjects with severe MR requiring MV replacement and at high risk for open-heart surgery. The primary safety endpoint is freedom from all-cause mortality and major adverse events at 30 days. The US-based AHEAD trial (NCT03813524) is currently evaluating the safety and technical performance of the Cardiovalve TMVR system in 15 participants and is scheduled to complete in April 2027.

AltaValve Transcatheter Mitral Valve

The AltaValve device (4C Medical) is a repositionable, partially retrievable device that is implanted in a supra-annular position via transapical and transfemoral/transseptal routes. It consists of a selfexpanding spherical nitinol frame (50–90 mm) that holds a 27 mm trileaflet bovine pericardial valve with an inferior fabric skirt to prevent paravalvular leaks.31 The first in-human implantation was in a 77-yearold man with high surgical risk and severe MR with a history of coronary artery bypass and surgical aortic valve replacement, reduced left ventricular ejection fraction (30%) and chronic AF. Preprocedural CT measurements were used to select a valve with a 70 mm frame and 46 mm annular ring with insertion via transapical approach and positioning under TOE guidance. Repeat CT and TOE imaging 6 days later revealed correct valve positioning and good apposition of the frame to the left atrial wall. The patient was discharged after 9 days with no adverse events at 30-day follow-up.31 The AltaValve is undergoing testing in an early feasibility study with estimated enrolment of 15 patients and planned primary completion in December 2022 (NCT03997305).

Cephea Transcatheter Mitral Valve

The Cephea TMVR system (Abbott Vascular) is designed for transseptal delivery and consists of a self-expanding double-disc stent structure carrying a trileaflet pericardial valve. The ventricular disc anchors the system in the sub-annular region and the atrial disc is deployed onto the base of the left atrium, fixating the valve through axial force without need for further sub-valve anchors. A multilevel conformability design enables adaptation to varying anatomy and a central decoupled core carrying the actual valve also prevents the leaflets from compressing the annulus. The low profile of the valve frame aims to prevent LVOT obstruction even in challenging anatomy. Its first in-human implantation was reported in 2019 in an 83-year-old woman who had non-ischaemic congestive heart failure, AF and severe MR due to P3 prolapse with chordal rupture and a flail leaflet.32 Surgical risk was considered prohibitive and other percutaneous approaches carried a high risk of LVOT obstruction. Successful Cephea valve implantation resulted in immediate abolition of MR and significant improvement of heart failure symptoms (NYHA class 1) at 28-week followup with normal valve function, sustained left ventricular outflow and no intra- or paravalvular leak. The Cephea Transseptal Mitral Valve System FIH trial (NCT03988946) initially intended enrolment of 15 patients in an open label single-arm design, but recently completed enrolment after one patient – further information on additional trials is awaited. However, recently, early experience with the Cephea device in three patients has been reported in addition to the first in-human report.33 Implantation was successful in all patients with only mild paravalvular leak and no signs of LVOT obstruction or increased mitral gradients post procedure. After a median 6-month follow-up, valve function was sustained, echocardiographic parameters (mitral and LVOT gradients, paravalvular leak) remained favourable and all patients were in NYHA functional class II while experiencing improvement in quality of life according to the Kansas City Cardiomyopathy Questionnaire scores.

Sapien M3 Transcatheter Mitral Valve

The Sapien M3 transseptal TMVR system (Edwards Lifesciences) is based on the established S3 valve for transcatheter aortic valve replacement with a polyethylene terephthalate skirt knitted onto the 29 mm S3 frame for paravalvular sealing. A spiral-like nitinol dock featuring two wider turns (one capturing the native leaflets and one maintaining position in the left atrium) and several central functional turns to anchor the valve implant is initially deployed, followed by Sapien M3 valve delivery using the Edwards Commander system and implantation with balloon expansion. Following publication of initial first in-human experience, 30-day outcomes of 35 high surgical risk patients with severe symptomatic MR treated within the ongoing single-arm US Early Feasibility Study of the Sapien M3 TMVR System (NCT03230747, planned enrolment of 50 patients) are now available.34,35 Technical success was achieved in 31 of 35 patients (one required paravalvular leak closure, one required separate transseptal punctures for dock and valve deployment and no valve was deployed in two patients). At 30 days, 1 patient (2.9%) had died and one had experienced a disabling stroke with a further case of valve thrombosis. Almost all (93.8%) patients had MR 0 or 1+ with a mean gradient of 5.6 ± 0.4 mmHg and 63.5% were in NYHA class I/II. While familiarity with the established Sapien valve platform (and proven durability in the aortic position) might offer advantages over other TMVR systems, complex interaction of the docking implant with the sub-valve apparatus could reduce ease of use.

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Transcatheter Mitral Valve Replacement: Concepts and Evidence The ENCIRCLE trial studying safety and effectiveness of the Sapien M3 device in 400 estimated patients just started enrolment (NCT04153292).

later valve replacement, which is only possible following MitraClip using electrosurgical laceration of the edge-to-edge bridge.42

Early Transcatheter Mitral Valve Replacement Outcomes

Several challenges need to be addressed in the development of TMVR. Early generation TMVR devices (including Tendyne, the only system with CE mark approval), require large profile delivery systems and the majority remain limited to transapical access. Transcatheter aortic valve replacement demonstrated improved outcomes with transfemoral intervention and it is widely expected that there will be a significant reduction in periprocedural complications when transseptal TMVR delivery becomes feasible. In addition, large bulky devices have elevated risk of thrombus formation and specific pharmacological antithrombotic strategies are required after valve implantation.43 These factors – large profile delivery system with an increased risk of access-site bleeding and large devices with risk of thrombus formation – as well as the potential risk of afterload mismatch following TMVR with complete obliteration of MR still represent potential disadvantages of TMVR when compared to transcatheter repair approaches.

Over 250 patients have now been treated with TMVR and recent pooled data of patients treated with seven different devices demonstrate that the vast majority had functional MR (76%), symptomatic advanced heart failure (NYHA class ≥III 80%, mean LVEF 42.6 ± 11.0%), and a high prevalence of AF (59%). Technical success was achieved in 92%, with conversion to surgery in 4%, LVOT obstruction in 4% and a procedural death rate of 2%. Pooled mean follow-up duration was 9.4 months with mortality of 13% at 30 days and 23% over subsequent follow-up, the vast majority due to cardiac causes. All surviving patients had MR grade <2 at follow-up with an observed device thrombosis rate of 5%.36 A recent systematic review by del Val et al. including data on 308 patients treated with TMVR confirmed the high technical success rate of 92% and reported a similar mortality at 30 days (14%) and after a mean follow-up of 10 months (28%).37 As currently only small early feasibility studies are available for most TMVR devices, it is not yet possible to robustly identify predictors of favourable clinical outcomes. Assessing outcomes of the first 100 patients treated using the Tendyne system, the only TMVR device with larger clinical experience, Badhwar et al. identified prior percutaneous intervention (OR: 6.44, p=0.028) and renal insufficiency (OR: 8.15, p=0.022) as predictors of worse outcome after 1 year (evaluated using a combined endpoint of mortality and hospitalisation for heart failure), while preprocedural severe MR, when compared to moderate-severe MR, predicted freedom from the combined endpoint.38 The rate of LVOT obstruction in the first studies of TMVR has been very low, admittedly a result of rigorous preprocedural screening, hindering identification of anatomies increasingly prone to this complication.37 Imaging based models, incorporating factors such as device protrusion, flaring and angulation, aortomitral angulation, and a potential septal bulge, have been developed to assess the potential risk of LVOT obstruction, however, these concepts need to be validated in the clinical setting.39,40

The Future of Transcatheter Mitral Valve Replacement

The COAPT trial has established MV repair using the MitraClip device as the transcatheter treatment of choice for patients with high surgical risk and symptomatic severe MR.8 However, several limitations remain and the advent of TMVR has the potential to further transform the field of MV intervention. MV disease is complex and often multifactorial with a wide variety of disease patterns and specific anatomical criteria have to be met to ensure reproducibility of promising repair outcomes. TMVR devices may target numerous anatomical variations and negate this heterogeneity. In addition, TMVR requires highly experienced operators to guarantee optimal results whereas standardised treatment with TMVR may allow a more predictable reduction of MR. Furthermore, the long-term durability of transcatheter repair remains unknown – indeed, randomised surgical data have demonstrated significantly higher rates of recurrent MR following MV repair when compared to replacement (58.8% versus 3.8%).41 Thus, if repair techniques are used they should ideally allow for 1.

Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005–11. https://doi.org/10.1016/S01406736(06)69208-8; PMID: 16980116. 2. Coffey S, Cairns BJ, Iung B. The modern epidemiology of

Furthermore, it is important to note that currently a considerable proportion of patients are not suitable for TMVR devices due to anatomical challenges, such as large annuli, the risk of LVOT obstruction and dimensions of the left ventricle. In line with these considerations, del Val et al. in their systematic review, when comparing main baseline patient characteristics and outcomes of the pooled TMVR population with those of the device group in the COAPT trial, found safety and procedure-related complications currently still favouring the transcatheter repair approach.37 Thus, existing and future TMVR systems will need to prove themselves in comparison with MitraClip, which has demonstrated substantial clinical benefits in terms of safety, mortality and need for hospitalisation. TMVR is a challenging procedure requiring multidisciplinary collaboration, not only during evaluation of patients and preprocedural decision making, but also in safely conducting the procedure. Thus, it is essential that these procedures are performed in centres with established heart teams who have an established MV programme. The multidisciplinary heart team should at least be comprised of interventional cardiologists, cardiac surgeons, cardiac anaesthetists, cardiac imaging and heart failure specialists. Standardised treatment algorithms with regular multidisciplinary meetings using a wide range of treatment options for MV disease should be implemented. Following the vast experience and widespread use of transcatheter MV repair (predominantly using the MitraClip device), TMVR, complementing the therapy armamentarium for MV disease, will probably be offered in the near to mid-term future to patients in whom sub-optimal outcomes of valve repair seem likely. Primarily, TMVR will be offered to patients for whom surgery is not possible due to age and/or comorbidities or in which transcatheter repair seems unfeasible due to unfavourable anatomical or functional parameters. Given the existing limitations of established MV repair technologies and the wide spectrum of MR patients and valve anatomy needing treatment, further development and evaluation of TMVR devices is necessary to enable tailored transcatheter treatment for individual patients.

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Coronary

Minimally Invasive Coronary Revascularisation Surgery: A Focused Review of the Available Literature Karel M Van Praet,1,2 Markus Kofler,1 Timo Z Nazari Shafti,1,2,3 Alaa Abd El Al,1 Antonia van Kampen,2,4 Andrea Amabile,5 Gianluca Torregrossa,5 Jörg Kempfert,1,2 Volkmar Falk,1,2,3,6,7 Husam H Balkhy5 and Stephan Jacobs1 1. Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Germany; 2. ZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany; 3. Berlin Institute of Health, Berlin, Germany; 4. Leipzig Heart Center, University Clinic for Cardiac Surgery, Leipzig, Germany; 5. Division of Minimally Invasive and Robotic Cardiac Surgery, Department of Surgery, University of Chicago, Chicago, IL, US; 6. Department of Cardiovascular Surgery, Charité – Universitätsmedizin Berlin, Berlin, Germany; 7. Translational Cardiovascular Technologies, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland

Abstract

Minimally invasive coronary revascularisation was originally developed in the mid 1990s as minimally invasive direct coronary artery bypass (MIDCAB) grafting is a less invasive approach compared to conventional coronary artery bypass grafting (CABG) to address targets in the left anterior descending coronary artery (LAD). Since then, MIDCAB has evolved with the adoption of a robotic platform and the possibility to perform multivessel bypass procedures. Minimally invasive coronary revascularisation surgery also allows for a combination between the benefits of CABG and percutaneous coronary interventions for non-LAD lesions – a hybrid approach. Hybrid coronary revascularisation results in fewer blood transfusions, shorter hospital stay, decreased ventilation times and patients return to work sooner when compared to conventional CABG. This article reviews the available literature, describes standard approaches and considers topics, such as limited access procedures, indications and patient selection, diagnostics and imaging, techniques, anastomotic devices, hybrid coronary revascularisation and outcome analysis.

Keywords

Coronary artery bypass grafting, minimally invasive direct coronary artery bypass, totally endoscopic coronary artery bypass, off-pump coronary artery bypass, revascularisation, hybrid, multivessel, robot, redo, percutaneous coronary intervention, minimally invasive Disclosure: The authors have no conflicts of interest to declare. Received: 28 January 2021 Accepted: 29 March 2021 Citation: Interventional Cardiology Review 2021;16:e08. DOI: https://doi.org/10.15420/icr.2021.05 Correspondence: Karel M Van Praet, Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E: vanpraet@dhzb.de Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In the early 1960s the first reports on successful aortocoronary bypass operations for the treatment of coronary artery disease (CAD) were published.1 Ever since, coronary artery bypass grafting (CABG) has become one of the most frequently performed operations worldwide and has been continuously refined and developed.2 Off-pump surgery and minimally invasive procedures have evolved to minimise the surgical trauma associated with CABG. In Germany, the unadjusted in-hospital survival rate for the 34,224 isolated CABG procedures was 97.3% in 2019.3 Calafiore et al. first described a left internal mammary artery (LIMA) to left anterior descending coronary artery (LAD) anastomosis via a small left anterior thoracotomy on the beating heart in 1996 and since then, minimally invasive CABG has been gaining wide acceptance in clinical practice, with many groups attempting to improve the procedure.2,4–9 The emergence of percutaneous coronary interventions (PCI) has notably intensified the search for less invasive procedures for surgical revascularisation. Despite the high rates of CAD, its optimal treatment is still the topic of ongoing debate. Both CABG and PCI have been subject to multilatitudinal scrutiny over the years.10–23 PCI is usually favoured due to

its minimal invasiveness, especially in settings where patients can choose between these two modalities. Yet, multiarterial (MA) surgical revascularisation compared with PCI has resulted in substantially enhanced death rates and survival free of reintervention.24 Accordingly, MACABG represents the optimal therapy for multivessel coronary artery disease (MVCAD) and should be enthusiastically adopted by multidisciplinary heart teams as the best evidence-based therapy.24 However, one may not forget that the ART trial has shown that bilateral internal thoracic artery (BITA) grafting is not superior to single internal thoracic artery (SITA) grafting at least in the first decade following CABG.25,26 It may be possible that at further follow-up (at 15 or perhaps 20 years), a better survival of the BITA group may become apparent but until that time, SITA appears to be an equally good option.26 For the treating physician, factors such as predicted surgical mortality, the complexity of CAD as well as the anatomy and anticipated results filter into the decision-making process.27 The resulting risk–benefit ratio should be used to determine whether conservative therapy, PCI or CABG should be performed. Mohr et al. have focused on minimally invasive CABG and

MIDCAB, TECAB and Hybrid Coronary Revascularisation Surgery the implementation of robotic support using the da Vinci system (Intuitive Surgical).28–34 To overcome technical and anatomical limitations in totally endoscopic coronary artery bypass (TECAB), automated anastomotic devices to facilitate the procedure were developed.35–37 The innovative TECAB approach was performed in a number of cases with promising results.29 However, the original enthusiasm for this procedure was followed by a slow adoption rate on a larger scale. This occurred for several underlying reasons including the need to develop dedicated skills, the steep learning curve related to the procedure, the increased scrutiny of outcomes in CABG and the costs related to the robotic equipment. Nowadays, minimally invasive direct coronary artery bypass (MIDCAB) grafting is the routine procedure for patients with isolated proximal LAD stenosis and also as part of a hybrid approach in selected patients with MVCAD.27,38 In general, avoidance of sternotomy and cardiopulmonary bypass (CPB) has allowed for faster recovery, resulted in less bleeding and fewer transfusions and helped to prevent wound infections.39 While MIDCAB initially mainly encompassed the revascularisation of the LAD with the LIMA, minimally invasive techniques are not restricted to patients with single-vessel disease, but can also be applied to selected cases of MVCAD.5,40 The use of both IMAs through a non-sternotomy approach was described by Balkhy et al. in 2017, using a totally robotic approach and recently by Davierwala et al. via a mini-thoracotomy incision. 41,42 In both cases, the sternal sparing technique enhances the adoption of both internal thoracic arteries as conduits and nullifies the risk of deep sternal wound infection, while providing the benefit of multiarterial bypass grafting. This review discusses the available literature, describes standard approaches and elaborates on topics such as limited access procedures, indications and patient selection, diagnostics and imaging, different techniques, anastomotic devices, hybrid revascularisation, pitfalls and outcome analysis.

Methods

We searched the Medline database using subject and text terms for MIDCAB, TECAB, hybrid coronary revascularisation (HCR), robotic-assisted MIDCAB, anastomotic devices, fractional flow reserve (FFR), instantaneous wave-free ratio and PCI. We limited our search to published review articles, case series and reports, retrospective comparative studies and randomised controlled trials (RCTs) between January 1998 and January 2021 to reflect contemporary practices regarding minimally invasive coronary revascularisation surgery in patients presenting with CAD. We also searched for meta-analyses in the above database and manually retrieved the most current meta-analyses that included RCTs, observational studies or both for the eight major topics. We also reviewed reference lists of identified studies. Duplicate references were identified and removed using the EndNote X5 Library (Thomson Reuters) program. Statistical software was not required because no numerical syntheses were performed.

Indications and Patient Selection

Heart teams are confronted with the challenge of incorporating minimally invasive strategies – off-pump CAB (OPCAB), MIDCAB, TECAB, PCI, and the hybrid approach – into the decision process, yet current guidelines do not fully address this challenge. The 2018 ECS/EACTS guidelines on

myocardial revascularisation provide some criteria for the decisionmaking for minimally invasive and hybrid CABG procedures as shown in Table 1.27 In 2020, Van den Eynde et al. published a new decision tree that incorporates recent advances in minimally invasive revascularisation strategies, to optimise adequate delivery of care for each individual patient’s needs.44 In their decision tree, distinctions are made between single, double, and triple vessel disease and decision elements such as the SYNTAX-score, contraindication for dual antiplatelet therapy (DAPT), failed PCI and diabetes are added to guide the heart team’s decisions.44 Careful patient selection is of utmost importance to accomplish satisfactory minimally invasive coronary revascularisation. Regarding characteristics of the LAD itself, Diegeler et al. concluded that a diameter <1.5 mm, diffuse disease, severe calcification or intramural position of the LAD are exclusion criteria for MIDCAB.34 Second, they suggested that unfavourable anatomical conditions regarding sufficient exposure of the LAD and LIMA made MIDCAB unsuitable for women with obesity and/or large breasts and the authors recommended using a full sternotomy OPCAB approach in this patient group.34 While these recommendations reflect the early MIDCAB experience, in the current era only very few restrictions apply. Amabile et al. reported that contraindications for the current TECAB practice were severe left pleural scarring (history of lung surgery or chronic granulomatous inflammatory processes), severe left ventricular dysfunction requiring the potential use of advanced myocardial support after surgery, and emergent cases.45 Minimally invasive surgical revascularisation has been found to be safe in single vessel disease as well as a selected group of patients with MVCAD, where it has been shown to have low complication rates, good long-term results and acceptable conversion rates.46,47 Furthermore, Al-Ruzzeh et al. found that patients had excellent subjective mid-term outcomes concerning their general health and quality of life.48 Nonetheless, it is important to keep in mind that any minimally invasive coronary operation remains more challenging than conventional CABG and that the choice of treatment strategy remains a controversial topic.

Techniques of Minimally Invasive Coronary Artery Bypass Grafting

The lack of a standardised nomenclature of different types of minimally invasive CABG procedures has generated confusion among cardiac surgeons and interventional cardiologists working in a heart team. In this manuscript we present the most adopted techniques and their variation to offer a general idea on how minimally invasive coronary revascularisation can be accomplished.

Minimally Invasive Direct Coronary Artery Bypass Grafting

MIDCAB grafting is currently the most standardised of all minimally invasive coronary procedures. It is performed through a small (mini) thoracotomy in the fourth left intercostal space (ICS) underneath the nipple. Surgeons perform both the LIMA takedown as well as the distal anastomosis of the LIMA to the LAD through this access. Grafting of midLAD and diagonal branches can be performed with this approach. The takedown of the LIMA can be challenging under direct vision, particularly in obese patients, women with large breasts or in tall patients with a long chest. Several surgeons have implemented the traditional MIDCAB technique with a videoscope inserted through a trocar in the second or

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MIDCAB, TECAB and Hybrid Coronary Revascularisation Surgery Table 1: Criteria for Considering Patients for Minimally Invasive Coronary Artery Bypass Grafting Through Limited Thoracic Access Minimally invasive CABG through limited thoracic access can be considered in patients with isolated LAD disease with recommendation for arterial IMA to LAD grafting Minimally invasive CABG through limited thoracic access should only be performed in centres with sufficient experience in minimal invasive and off-pump CABG surgery Hybrid procedures, defined as consecutive or combined surgical and percutaneous revascularisation, may be considered in specific patient subsets at experienced centres Van den Eynde et al.43: hybrid approaches combining MIDCAB and PCI, and MIDCAB with BIMA grafts can both be used as a revascularisation strategy in patients with triple vessel disease. If available in the hospital, these strategies should be considered by the heart team BIMA = bilateral internal mammary artery; CABG = coronary artery bypass grafting; IMA = internal mammary artery; LAD = left anterior descending coronary artery descending; MIDCAB = minimally invasive direct coronary artery bypass; PCI = percutaneous coronary intervention.

third ICS to better visualise the proximal portion of the LIMA. This type of procedure is generally referred to as video-assisted MIDCAB. The use of a new retractor system and single-lung anaesthesia greatly aids in facilitating mammary artery exposure and dissection and allows a dedicated team to perform bilateral thoracic artery takedown from an anterior/antero-lateral thoracotomy using direct vision with video assistance.49

Robotic-assisted Minimally Invasive Direct Coronary Artery Bypass Grafting

Robotic-assisted MIDCAB refers to the combination of a robotic takedown of the left internal thoracic artery and a direct anastomosis of the LIMA to the LAD accomplished at the bedside of the patient by the surgeon through a small anterior thoracotomy. This procedure has become popular because it has several advantages with respect to the traditional MIDCAB procedure, where the LIMA is harvested through the anterior thoracotomy:

• By using the robotic platform, the visualisation of the LIMA is

enhanced with lower risk of vessel injury and typically a longer IMA graft (until the distal bifurcation) can be harvested. If needed, the longer LIMA graft can be used to perform an additional sequential anastomosis on the diagonal coronary artery, thus enabling multivessel MIDCAB. • During a traditional MIDCAB procedure, a special retractor is used to asymmetrically separate the two portions of the anterior thoracotomy and expose the mammary artery. Such traction is responsible for the postoperative pain experienced by most patients who undergo MIDCAB. By using the robotic platform to accomplish the LIMA takedown, the anterior thoracotomy performed in robotic MIDCAB is small and the retraction force applied to expose the LAD and accomplish the LIMA to LAD anastomosis under direct vision remains minimal which decreases the postoperative pain for the patient. In robotic MIDCAB, the patient is positioned supine and a shoulder roll is applied on the left side of the spine to elevate the left hemithorax. Yet, some colleagues will not elevate the left chest as this may lead to pressure points. Single-lung ventilation is essential and the chest cavity is insufflated with CO2 to create additional space. The camera port is placed about 3 cm lateral to the mid-clavicular line, usually in the fourth or fifth ICS, and two other ports are placed two ICS above and below this first port. The robotic arms are advanced to the bedside of the patient from the right side, crossing the midline, and are docked with the trocar previously inserted. The surgeon sits at the robotic console generally positioned within the operative room just on a side of the patient’s table and manouevres the two arms and the camera to accomplish the surgery. A table-side assistant (a second surgeon or a physician assistant) stands beside the patient and is in charge of exchanging the instruments as requested by the primary surgeon who

sits at the surgical console. The mammary artery can be taken down both in skeletonised or pedicle technique using the robotic instruments.50 Side branches are clipped and cauterised. The entire length of the LIMA is mobilised. If required, both mammary arteries can be harvested by reaching the right internal thoracic artery with instruments still inserted using the trocars in the left chest and advanced through the midline crossing the anterior mediastinum into the right pleural space. The proximal portion of the right internal thoracic artery is harvested with the aid of the coronary stabiliser, which is inserted from a sub-costal trocar in the left chest and advanced to the proximal portion of the anterior mediastinum to expose the origin of the RIMA.41 After the IMA is harvested, the LAD is identified and finally a small anterior thoracotomy in the fourth and fifth ICS is performed to allow the surgeon to complete the LITA-toLAD anastomosis at the bedside using specialised instruments and a coronary stabiliser designed for minimally invasive coronary surgery. Most of the centres adopting robotic MIDCAB grafting perform the anastomosis in an off-pump fashion on a beating heart. If two mammary arteries have been harvested, the anterior thoracotomy can be extended laterally and the second IMA deployed to the anterolateral (or lateral) coronary target. As previously published by Van den Eynde et al., the extension of MIDCAB to vessels other than the LAD and its diagonal branches has in the past been hampered by two major challenges.43 First, in contrast to open surgery, manipulation of the heart through a thoracotomy is far more challenging.43 This has put an anatomical limitation to the extent of target vessels that can be reached, especially on the lateral and posterior sides of the heart.43 However, stabilisation devices that allow better exposure of the LAD as well as other vessels, have now become widely available.43 Second, the limited accessibility of the aorta during MIDCAB makes it difficult to perform proximal anastomoses for additional grafts.43 However, BIMA grafts combined with radial Y-grafts have been reported as an alternative to achieve revascularisation with multiple grafts.43 Une et al. evaluated the learning curve and its effect on minimally invasive cardiac surgery (MICS) CABG.51 They found that MICS CABG can be safely initiated without mortality or additional morbidity that could be explained by the learning curve. Pump assistance may be used without additional risk and represents a good strategy to avoid a steep learning curve and the possibility of conversion to sternotomy.51 Operative time reached an acceptable level at the 66th case in off-pump single-vessel small thoracotomy, the 16th case in CPB-assisted multivessel small thoracotomy (MVST) and the 40th case in off-pump MVST.51 Rodriguez et al. proved that in selected patients, MICS CABG can be safely initiated as a minimally invasive, multivessel alternative to open surgical coronary revascularization with excellent mid-term results.52 In their study, learning phase effects were not observed with regard to overall procedural safety, but rather in terms of improved freedom from bleeding, infection, conversion to sternotomy and repeat revascularisation.52

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MIDCAB, TECAB and Hybrid Coronary Revascularisation Surgery Totally Endoscopic Coronary Artery Bypass Grafting

The TECAB procedure was initially developed and performed to graft the LAD with the LIMA using the support of CPB in an arrested heart, as an even less invasive option than robotic-assisted MIDCAB. After demonstrating the safety and reproducibility of this approach in a case series, and through significant technological improvements of the following generations of the da Vinci robotic system, multiple conduit harvesting for more complex, off-pump grafting strategies became possible.53–55 It has been extensively demonstrated that robotic-assisted, endoscopic, multivessel CABG procedures are safe, feasible and reproducible and lead to excellent outcomes.6,8,56,57 In their propensity score matched analysis, Kofler et al. were able to demonstrate comparable perioperative and long-term results between highly selected robotic patients and conventional CABG patients, despite the longer operative times in robotic CABG.58 Moreover, several advantages of TECAB in comparison to any other strategy of revascularisation have been recently outlined.59 First, TECAB represents the paradigm of truly minimally invasive surgical myocardial revascularisation, being performed using five ports (8–12 mm) in the left chest, with no thoracotomy or sternotomy required. This lowers the risk of surgical site infection and minimises postoperative pain, allowing for a quick recovery, with early postoperative discharge in 2 or 3 days. Second, TECAB allows for multiple arterial grafting with the use of BITA with no risk of deep sternal wound infection even in high-risk patients. Moreover, in a closed-chest environment the right ITA is actually closer to the heart than generally perceived in an open sternotomy case and can reach left side targets passing underneath the anterior mediastinal fat. Thus, BITA can be used regardless of BMI, gender or glycated haemoglobin levels in patients with diabetes. Finally, an off-pump TECAB approach with BITA as conduits of choice provides all-arterial inflow which can be achieved in the left coronary system with a complete no-aortic touch technique, minimising the risk of stroke while offering the demonstrated benefit of a multiarterial revascularisation.60–62 Despite these numerous advantages, the penetration of TECAB is extremely limited due to the steep learning curve required to complete the distal anastomosis and properly stabilise the coronary target using the robotic platform. For these reasons, anastomotic devices need to be developed to facilitate TECAB.

design constraints apply.36,66,67 Data directly comparing device and handsewn anastomosis in minimally invasive CABG remains very limited.68,69 The majority of available data exists for the C-Port Flex-A anastomotic device (Aesculap), which is the only device supported by extensive clinical data on its safety and patency published by several teams in Europe and the US.70 This remains the only distal anastomotic device that has been cleared by the FDA. The C-Port connector is a single-shot anastomotic device which completes the coronary anastomosis with an interrupted row of 13 microscopic stainless steel staples. A recent histological study showed it to be comparable to a hand-sewn coronary anastomosis regarding inflammatory response development of neointimal hyperplasia.71,72 Thus, further adequately powered Phase IV clinical trials are needed to compare anastomotic devices to hand-sewn techniques with carefully selected patient groups, considering factors such as target coronary vessel territory, calcification and quality as well as the choice of conduit. The results should detail morbidity and mortality outcomes, particularly focusing on combined major adverse cardiac and cerebrovascular events (MACCE) in the short and long term.66 Unfortunately, Aesculap suspended the production of this device after the technology was purchased from the original manufacturer with no official intention to bring it back on the market. This decision has been a massive step backwards for minimally invasive coronary surgery and reflects the lack of industry support in this field. There are only two other devices in pre-clinical development: the S² Distal Anastomotic System (iiTech) and the ELANA system (AMT Medical). A first-in-human clinical trial is imminent for the latter.

Hybrid Coronary Revascularisation

The rationale for hybrid coronary revascularisation (HCR) lies in the wellestablished survival benefit conferred by LIMA-to-LAD grafts and the use of new stent platforms featuring lower stent restenosis and thrombosis rates compared with venous graft stenosis and occlusion rates, respectively.73

Stastny et al. proved that arrested heart TECAB resulted in excellent clinical long-term outcomes with a LIMA artery patency rate comparable with conventional CABG at 10 years after surgery.64

When comparing CABG to PCI, CABG remains the gold standard in MVCAD, with lower mortality and lower repeat vascularisation risks. Despite the higher stroke risk suggested by CABG, that risk does not outweigh its benefits in long-term survival, leading physicians to combine the two procedures in what is known as HCR. Here, both surgical bypass and PCI are encompassed in that they are either performed during the same procedure or within 60 days of each other. Repossini et al. concluded that HCR is a safe approach with acceptable long-term results and that it could be offered to high-risk patients and to MVD patients whose non-LAD lesions, after careful evaluation, were judged more suitable for PCI than for CABG. Considerable experience with MIDCAB and close cooperation between surgeons and cardiologists are mandatory to ensure the optimal revascularisation strategy is decided for each individual.74

Anastomotic Devices

In general, there are three different approaches to HCR:

Kofler et al. were able to demonstrate both minimally invasive procedures (MIDCAB versus TECAB) as feasible and safe, regarding perioperative clinical outcome. No perioperative death occurred and they observed an MI rate of 1.5% versus 0% (p=0.463) and a stroke rate of 1.5% versus 0% (p=0.454) in TECAB compared with MIDCAB, respectively.63 Their results were in line with previously published literature.

One of the first CABG procedures ever performed was done on the beating heart using an anastomotic device.35 In 1960, Robert Goetz used a tantalum Payr’s cannula to construct an end-to-end anastomosis between the right LIMA and the right coronary artery (RCA), demonstrating the feasibility of performing arterial grafting on the beating heart.35,65 The ideal anastomotic device should be easy to use, produce a geometrically optimal reproducible anastomosis with minimal endothelial damage and minimal blood-exposed non-intimal surface, yet a number of

• The hybrid approach: LIMA–to-LAD surgery via a non-sternotomy

approach (MIDCAB, robotic MIDCAB or TECAB), followed by PCI stenting of the non-LAD territory. The latter is generally performed 30 days after minimally invasive LIMA-to-LAD surgery. • The reverse hybrid approach: in this scenario, PCI stenting is performed prior to minimally invasive CABG to the anterior ventricular wall or to the left coronary artery. The reverse hybrid approach generally happens in the light of an acute coronary syndrome involving a

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MIDCAB, TECAB and Hybrid Coronary Revascularisation Surgery non-LAD target receiving acute PCI and consequent stent implantation. During emergency stenting, a diagnostic catheterisation of the left coronary system is accomplished yet additional stable CAD is noted. At this point, the surgeon is consulted to complete the revascularisation, applying a minimally invasive approach for LIMA-to-LAD surgery several weeks after the primary acute PCI. In this case, awareness should be raised regarding the need of DAPT. Nevertheless, the risk of bleeding during surgery should be addressed appropriately. • The advanced hybrid procedure: this refers to any type of HCR that combines minimally invasive, sternal sparing, multiarterial bypass grafting with PCI.75,76 The standard hybrid approach only uses the LIMA to bypass the LAD. The advanced hybrid approach uses both mammary arteries for deployment to the left coronary system (LAD and circumflex) whereas the RCA is treated with a stent some weeks after the initial minimally invasive surgical procedure. The advanced hybrid procedure is also adopted when a single mammary artery is used in a minimally invasive way to bypass the LAD and diagonal coronary artery sequentially, followed by PCI of another non-LAD target (obtuse marginal or RCA). The advantages and disadvantages of one stage (simultaneous) and twostage HCR were described and published in 2015 by Panoulas et al.73 The results from the POLMIDES trial showed that HCR is feasible in selected patients with MVCAD referred for conventional CABG.77–79 Foik et al. concluded that patients receiving the HCR treatment required administration of pressor amines less frequently and less often experienced hypotonia compared with the group receiving the classic treatment (conventional CABG or OPCAB).78 On the other hand, oxygen saturation was significantly lower in the HCR group compared with the group receiving the classic treatment. Mobilisation of patients in the twostage regimen of hybrid treatment was slower during the first two days and during cycles of rehabilitation but these patients achieved full selfreliance earlier than those from the classic group. Observational data on HCR from a multicentre study suggested that there is no significant difference in MACCE rates over 12 months between patients treated with multivessel PCI or HCR.80 The findings of Modrau et al. suggest non-superior 3-year clinical outcome after HCR compared to conventional myocardial revascularisation. Consideration of the procedure-associated morbidity may assist the heart team to provide an individualised revascularisation strategy.81 Various studies have shown that HCR resulted in fewer blood transfusions, shorter hospital stay, decreased ventilation times and shorter time for patients to return to work when compared to CABG, whereas CABG was more cost effective overall.82 The greater costs of HCR could be due to the use of radiographic instruments and stent implantation; however, it is suggested that with increasing experience these costs could be lowered. Both Reynolds et al. and Leacche et al. found that MACCE was significantly worse with HCR in high-risk patients, however in the mid-term (18 months), no difference in MACCE between the HCR and conventional CABG group was found.82,83 In fact, HCR patients showed lower stroke rates at 30 months.38,83,84 In their large series of HCR and multivessel PCI for patients with left main stenosis, Repossini et al. demonstrated favourable outcomes for HCR for patients with a medium–high EuroSCORE and a SYNTAX score <32, HCR may provide a promising alternative to conventional CABG and multiple PCI with similar postoperative results.85

HCR presents an attractive alternative option for treating patients with MVCAD because it maximises the clear survival benefits of LIMA-LAD grafting, improves quality assurance with completion angiography and allows quicker patient recovery; furthermore, patients avoid the negative systemic inflammatory effects of CPB and delayed healing after sternotomy.38 HCR most commonly involves a planned combination of LIMA-LAD grafting and PCI of non-LAD targets.86 One-third of US hospitals with on-site cardiac surgery perform HCR where it is reserved for a highly selected population.86 Clinical outcomes after HCR appear favourable, with lower MACCE, MI and repeat revascularisation rates compared with multivessel PCI.86 It has also been linked to lower stroke rates and in-hospital complications compared with CABG, but a greater need for repeat revascularisation.86 Engagement from interventional and surgical communities and adequate patient selection based on local expertise and data from registries and RCTs are of key importance to determine its future success.86 In light of data showing that drug-eluting stents are equivalent if not better than saphenous vein grafts, should we not be pushing the envelope and greatly expanding our use of HCR at the expense of traditional LIMA–LAD + saphenous vein graft CABG?88 The use of bilateral internal thoracic grafts improves overall longterm survival and repeat revascularisation-free survival without increasing the incidence of operative complications, including deep sternal wound infection, especially with the addition of graft skeletonisation.79,88,89 The short- and mid-term endpoints in this study would be unlikely to tease out these differences, so perhaps we should be more aggressive with BIMA grafting in any patient undergoing surgical myocardial revascularisation, including those who fit the ideal two-vessel HCR case and not just the young and relatively healthy.88 A hybrid approach could also be applied in an acute setting (reverse HCR) – treating the culprit lesion with PCI and then completing the revascularisation of other targets with minimally invasive CABG. There are many limitations of HCR. For one, the operation is challenging as surgeons have to work through small incisions. This makes it particularly difficult for inexperienced doctors as good results strongly depend on the quality of the anastomosis. Furthermore, there are no gold standard criteria for patient selection.90 Esteves et al. showed with the long-term follow-up of the randomised MERGING clinical trial that HCR was feasible but associated with increasing rates of MACCE during 2 years of clinical follow-up, while the control group treated with conventional surgery presented with low rates of complications during the same period. They postulated that, before more definitive data arise, HCR should be applied with careful attention in practice, following a selective case-by-case indication.91 Recent studies have fostered the opinion that CABG remains the gold standard in patients with MVCAD; however hybrid approaches are an attractive option for certain patient groups.73 Current evidence suggests that HCR is feasible and safe for a particular target group with acceptable mid-term outcomes that are non-inferior to conventional CABG: just over 60 years of age; mainly stable, CAD-favourable anatomy; intermediate risk and SYNTAX scores; and preserved or mildly impaired left ventricular ejection fraction.73 However, data for higher-risk groups, who would theoretically benefit the most from HCR, are weak or lacking; hence, no inferences or generalisations can be made regarding the role of HCR in these patients.73 The 2012 American College of Cardiology and American Heart Association guidelines recommend HCR in patients with heavily calcified proximal aortas, inadequate bypass conduits and landing targets for non-LAD vessels that are feasible for PCI.92 Furthermore, the 2018 European Society of Cardiology/European Association for CardioThoracic Surgery guidelines on myocardial revascularisation highlight the

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MIDCAB, TECAB and Hybrid Coronary Revascularisation Surgery need for multicentre studies to prove the efficacy and superiority of hybrid techniques in stable MVCAD.27 Nonetheless, Ganyukov et al. proved that inpatients with MVCAD amenable to CABG, HCR and multivessel PCI, the quantitative endpoint of residual myocardial ischaemia at 12 months, which is predictive in a gradient manner of cardiac death and adverse cardiac events, was similar with all three guideline-accepted revascularisation strategies. MVCAD PCI, using contemporary best-in-class drug-eluting stents, was associated with a shorter hospital stay, less inpatient rehabilitation and shorter periods of sick leave than CABG or HCR.93 While extended follow-up will determine longer-term outcomes from their study, a larger-scale multicentre trial powered for clinical endpoints would be warranted.

Conclusion

In the five decades since it has been introduced, CABG has been subject to continuous improvements and changes. The way in which the procedure is now performed has been transformed by technological advances that have propelled forward multiple CABG techniques. In the current era, CABG has become less invasive and emphasis has been given to more patient-friendly approaches and more durable results. MIDCAB was first described by Calafiore et al. and since then, many 1. 2.

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studies have highlighted the beauty of minimally invasive coronary procedures, accentuating it as an attractive alternative to conventional CABG as it bypasses the need for sternotomy.4 These less invasive methods are linked to reduced postoperative hospital stay, higher safety and higher efficacy and a better quality of life. When not performed as the primary operation, multiple studies have shown that MIDCAB can be performed in cases of reoperation.94–99 As opposed to CABG reoperations, MIDCAB has proven to be more effective and not linked to increased mortality and morbidity.100,101 MIDCAB is also a viable alternative to CABG and can also replace PCI in patients for whom PCI is either risky or impossible. A major obstacle physicians face when initiating MIDCAB is finding criteria for optimal patient selection. A further issue is that MIDCAB is technically demanding and accounts for longer learning curves making it prone to anastomotic failure if surgeons are not experienced. MIDCAB is also more costly in comparison to bare metal stenting. One of the newer developments in cardiac surgery is robotic-assisted MIDCAB and TECAB, aimed at yielding effective and lasting coronary anastomoses as well as faster recovery and less bodily trauma. It can, nonetheless, also affect cardiac and pulmonary function and cause prolonged mechanical ventilation. However, this seemed to be linked to certain pre-operative patient-related risk factors.

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revascularization in multivessel coronary artery disease: residual myocardial ischemia and clinical outcomes at one year – Hybrid coronary REvascularization Versus Stenting or Surgery (HREV). J Interv Cardiol 2020;2020:5458064. https:// doi.org/10.1155/2020/5458064; PMID: 31969796. Jacobs S, Holzhey D, Walther T, et al. Redo minimally invasive direct coronary artery bypass grafting. Ann Thorac Surg 2005;80:1336–9. https://doi.org/10.1016/j. athoracsur.2005.03.142; PMID: 16181865. Nakagawa H, Nabuchi A, Terada H, et al. Minimally invasive direct coronary artery bypass surgery with right gastroepiploic artery for redo patients. Ann Thorac Cardiovasc Surg 2015;21:378–81. https://doi.org/10.5761/atcs.oa.1400286; PMID: 25912220. Takahashi M, Rhee AJ, Filsoufi F, et al. Anesthetic and technical considerations in redo coronary artery bypass surgery using sternal-sparing approaches. J Cardiothorac Vasc Anesth 2013;27:315–8. https://doi.org/10.1053/j. jvca.2012.05.004; PMID: 22770757. Morishita A, Shimakura T, Miyagishima M, et al. Minimally

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invasive direct redo coronary artery bypass grafting. Ann Thorac Cardiovasc Surg 2002;8:209–12. PMID: 12472384. 98. Cheung D, Flemma RJ, Mullen DC, Lepley D. An alternative approach to isolated circumflex coronary bypass reoperations. Ann Thorac Surg 1982;33:302–3. https://doi. org/10.1016/S0003-4975(10)61931-5; PMID: 6978690. 99. van der Merwe J, Casselman F, Vermeulen Y, et al. Reasons for conversion and adverse intraoperative events in robotically enhanced minimally invasive coronary artery revascularization. Innovations (Phila) 2020;15:251–60. https:// doi.org/10.1177/1556984520920724; PMID: 32434406. 100. Pascucci S, Günkel L, Zietak T, et al. Use of MIDCAB procedure for redo coronary artery bypass. J Cardiovasc Surg (Torino) 2002;43:143–6. PMID: 11887045. 101. Miyaji K, Wolf RK, Flege JB. Minimally invasive direct coronary artery bypass for redo patients. Ann Thorac Surg 1999;67:1677–81. https://doi.org/10.1016/S00034975(99)00327-6; PMID: 10391274.

Structural

Moderate Aortic Stenosis: What is it and When Should We Intervene? Sveeta Badiani ,1,2 Sanjeev Bhattacharyya ,1,2,3 Nikoo Aziminia ,1 Thomas A Treibel

1,3

and Guy Lloyd

1,2,3

1. Heart Valve Clinic and Echocardiography Laboratory, Barts Heart Centre, St Bartholomew’s Hospital, London, UK; 2. William Harvey Research Institute, Queen Mary University of London, UK; 3. Institute of Cardiovascular Sciences, University College London, London, UK

Abstract

Current guidelines recommend aortic valve replacement in patients with severe aortic stenosis in the presence of symptoms or a left ventricular ejection fraction <50%. However, patients with less than severe aortic stenosis may also experience symptoms and recent literature suggests that the prognosis is not as benign as previously reported. There are no recommendations for patients with moderate aortic stenosis and left ventricular dysfunction, despite the high associated morbidity and mortality. There is also some evidence that these patients may benefit from early aortic valve intervention. It is recognised that aortic stenosis not only affects the valve but also has a complex myocardial response. This review discusses the natural history of moderate aortic stenosis along with the role of multimodality imaging in risk stratification in these patients.

Keywords

Aortic stenosis, biology, progression, echocardiography, imaging, interventions, outcomes Disclosure: GL is supported by research and program grants by Medtronic and holds research and speaking grants by Edwards Lifesciences. TAT is funded by a British Heart Foundation Intermediate Research Fellowship (FS/19/35/35374), and indirectly supported by the University College London Hospitals and Barts NIHR Biomedical Research Centres. All other authors have no conflicts of interest to declare. Received: 29 January 2021 Accepted: 29 March 2021 Citation: Interventional Cardiology Review 2021;16:e09. DOI: https://doi.org/10.15420/icr.2021.04 Correspondence: Guy Lloyd, Heart Valve Clinic and Echocardiography Laboratory, Barts Heart Centre, St Bartholomew’s Hospital, West Smithfield, London, EC1A 7BE, UK. E: guy.lloyd1@nhs.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The timing of intervention in aortic stenosis (AS) is crucial. It is evident that severe AS is associated with poor survival when left untreated.1 Although current guidelines recommend aortic valve replacement (AVR) in patients with symptomatic severe AS or evidence of left ventricular dysfunction (left ventricular ejection fraction [LVEF] <50%), there is growing evidence that this treatment paradigm may lead to intervention after significant cardiac damage has occurred, with resultant poorer outcomes.2–4 Some patients with symptoms of decompensation (breathlessness, chest pain or syncope) only have moderate AS, yet have no other pathologies to which their symptoms can be attributed. AVR may be considered in patients with moderate AS who are undergoing surgery for other indications.2,3 Current guidelines suggest that patients with moderate AS (defined as peak transaortic velocity of 3.0–3.9 m/s or mean gradient [MG] of 20–39 mmHg) should undergo surveillance yearly, and AVR deferred until the AS becomes severe. Transcatheter aortic valve replacement (TAVR) is currently not indicated in moderate disease. However, there are no established recommendations for the treatment of moderate AS with left ventricular systolic dysfunction, despite growing evidence of morbidity and mortality in this population.5 As with most guideline recommendations in valvular heart disease, there is a lack of randomised control trial data to support or refute earlier intervention in these patients.

The Biology of Aortic Stenosis

It is recognised that AS is not only a disease of the valve but also of the myocardium.6 Longstanding AS causes an increase in afterload, which

leads to a myocardial remodelling response. This initial adaptive process eventually becomes maladaptive, and determines disease progression, symptoms and outcomes. The left ventricular response to AS is complex and consists of a combination of wall thickening, concentric remodelling and change in cavity size to maintain wall stress. In the later maladaptive stages, capillary rarefaction and cell death occur, as well as focal and diffuse myocardial fibrosis. How and when these processes develop is poorly understood, although sex differences appear particularly important.7 The afterload response conferred by the vasculature is important and varies between individuals. The prevalence of atherosclerosis and hypertension is also high in these patients, which can accelerate arterial stiffness. AS – conventionally defined in binary terms (moderate or severe) – is better characterised by a number of relatively distinct phenotypes and how these relate to clinical courses/outcomes. Because conventional high gradient does not develop in many cases, pathological changes must be occurring at an earlier point in the disease process in some, if not all individuals. This is supported by the strong signal of symptom limitation at the moderate severity.

The Progression of Aortic Stenosis

The natural history of severe, symptomatic AS has been extensively documented.8–9 However, there is much less information on clinical outcomes in adults with moderate AS and the existing literature is heterogeneous. It is important to differentiate the anatomical progression

Moderate Aortic Stenosis: What is it and When Should We Intervene? of stenosis (‘how narrow?’) and the clinical progression with adverse outcome (‘how bad?’).

Anatomical Progression

There is a wide range in the progression rate, and it is unclear why some patients have a rapid disease progression and some do not. Haemodynamic AS progression is classically considered as constant and homogeneous (average increase in peak velocity by 0.3 m/s per year and an increase in MG by 7 mmHg per year) but is highly variable among individuals. As yet, no medical therapies have proven effective in reducing progression of AS or improving clinical outcomes.10

of severe AS. Both AS severity and left ventricular dysfunction are variables with definitions of ‘severe’ and ‘abnormal’ based on observational clinical studies.25,26 However, there is some evidence to suggest that patients with conventionally defined moderate AS and heart failure may benefit from AVR.27–29

Earlier studies based on patient groups identified at cardiac catheterisation suggested a relatively benign prognosis in patients with moderate AS.11,12 Horstkotte et al. demonstrated a time interval between the first manifestation of moderate AS and progression to severe stenosis requiring surgery of 13.4 years.12

The study by van Gils et al. showed that 61% of patients with moderate AS and left ventricular systolic dysfunction died, underwent AVR or were hospitalised for heart failure, at 4-year follow-up with male sex, New york Heart Association Class III or IV, and higher peak aortic velocities independently predicting events.26 A retrospective analysis from the Duke Echocardiographic database reported a mortality benefit associated with AVR (with or without concomitant coronary artery bypass grafting) for moderate AS and left ventricular systolic dysfunction (LVSD), compared with medical management.28 These findings differ from those of Fougeres et al., who found that in patients with pseudo-severe (moderate) AS, there was no difference in the survival rate compared to controls with LVSD and no valve disease.29

Later studies suggest that both clinical outcomes and progression to severe AS occur at a very high rate.13–20 Comparison of outcomes in patients with moderate AS is difficult because of the marked differences between studies (differences in symptom status, definition of stenosis severity and modality used to assess AS, study design, choice of endpoints and definition of event-free survival). Nevertheless, moderate AS is associated with a substantial increase in mortality from both cardiac and non-cardiac causes. Furthermore, progression to severe disease can occur much more rapidly than previously expected.

Data from Hayward et al. identified 169 patients with moderate AS and left ventricular impairment (AVA 1–1.5 cm2 and LVEF <50%) and sought to identify determinants of outcomes. The primary endpoint was all cause mortality with a median follow-up period of 22.9 months. Patients with abnormal global longitudinal strain (GLS) had significantly worse survival and the only independent predictor of outcome was GLS.30 A recently published study by Ito et al. showed that in patients with moderate AS, those with decreased LVEF and/or indexed stroke volume were at increased risk of mortality.31

The studies also identify characteristics (e.g. moderate or severe aortic valve calcification and concomitant coronary artery disease) that may put certain patients at risk for more rapid progression of AS.21 Data from the Heart Valve Clinic International Database registry showed that in patients with moderate AS at baseline, independent determinants of cardiovascular mortality were dyslipidaemia and peak velocity. There was also a trend for association between cardiovascular mortality and LVEF.22

Evidence for Benefit from Earlier Intervention

Clinical Progression

Observational data from a large Australian registry sought to determine more definitively the prognostic impact of increasing severity of AS. Echocardiographic findings from 3,315 patients with moderate AS were linked to long-term mortality. The 5-year mortality was 56%, after adjusting for age, sex, left ventricular systolic or diastolic dysfunction and aortic regurgitation. The risk of dying in the longer term was similar to the risk in patients presenting with severe AS at baseline.5 In the population-based study by Livanainen et al., moderate AS was associated with an increased risk of all cause and cardiovascular mortality; however the independent predictive value was lost when left ventricular mass and systolic function were included in the analysis.14 The studies detailing clinical outcomes in patients with moderate AS are presented in Table 1. It is also important to note that patients with moderate mixed aortic valve disease (AS and regurgitation) are at risk for all-cause mortality, and that AVR significantly reduced this risk, independent for aortic valve area (AVA), symptom status and after controlling for confounding variables.23

Aortic Stenosis and Left Ventricular Dysfunction

Left ventricular dysfunction has been reported in a quarter of patients with AS.24 The natural progression of AS comprises different phenotypic presentations involving patients who will develop left ventricular dysfunction and symptoms early, much before reaching the limit definition

In patients with symptomatic AS (AVA <1 cm2) who had a low gradient and normal flow (NFLG), intervention was associated with reduced cardiacrelated mortality, as opposed to conservative treatment.32 Long-term data are equivocal. These findings are similar to another study that demonstrated a similar long-term mortality when comparing NFLG patients with patients with moderate AS.33 In contrast, another study found a similar survival in patients undergoing early AVR compared with watchful waiting .34 Moon et al. reported that among 255 patients with moderate AS and concomitant LVSD, 47.5% of patients died and 18.8% received AVR during a median of 1.8 years of follow-up. The incidence of all cause death was significantly lower in the early AVR group compared with the medical treatment group. The LVEF also improved to >50% in 59.5% of the early AVR group. Limitations include the single-centre nature and small patient numbers.35 The investigators of the TAVR-UNLOAD trial aim to provide further insight into moderate AS with left ventricular dysfunction. Three hundred patients will be randomised into two arms: TAVR combined with optimised heart failure therapy versus optimal heart failure therapy alone. The primary endpoint will be a composite of all-cause death, disabling stroke, heart failure hospitalisations, symptomatic aortic valve disease or non-disabling stroke.36 Hypertension and concurrent coronary artery disease are common in patients with AS. Hypertension may also be a risk factor for AS and adds to the total pressure load on the left ventricle. Medical therapy for hypertension follows standard guidelines, starting at a low dose and titrating upwards as needed to achieve blood pressure control. All patients should be screened and treated for hypercholesterolaemia.3

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Moderate Aortic Stenosis: What is it and When Should We Intervene? Table 1: Studies of Clinical Outcomes in Moderate Aortic Stenosis Study

Design

Inclusion Criteria

Turina et al. 198711

Retrospective

Horstkotte et al. 198812

Mean Age (Years)

Symptoms (%)

Follow-up

Event-free Survival

AVA 0.95–1.4 cm2 on cardiac 30 catheterisation No coronary artery disease

6.6 years

100% at 1 year 80% at 4 years

Retrospective

AVA 0.8–1.5 cm2

236

39 ± 18 rheumatic AS NR 48 ± 6 bicuspid AS 66 ± 12 degenerative

Average time interval 80% at 10 years between the manifestation of moderate AS and surgery was 13.4 years

Kennedy et al. 199113

Retrospective

AVA 0.7–1.2 cm2 on cardiac catheterisation EF 55 ± 17%

67 ± 10

2.9 years

72% at 4 years

Livanainen et al. 199614

Prospective

AVA 0.9–1.2 cm2 VTI ratio 0.36–0.44

75–86

4 years

Overall survival 50% at 4 years Overall survival without CV deaths 65% at 4 years

Otto et al. 199715

Prospective

Vmax 3–4 m/s

63 ± 16

2.5 ± 1.4 years

66% at 2 years

Rosenhek et al. 2004

Retrospective

Vmax 2.5–3.9 m/s

176

58 ± 19

4 ± 1.6 years

70% ± 4% at 3 years

Kearney et al. 201217

Prospective

MG 25–40 mmHg AVA 1.0–1.5 cm2

73 ± 6

6.5 ± 4.3 years

100% at 1 year 62% at 3 years 23% at 5 years

Mehrotra et al. 201818

Retrospective

AVA 1.0–1.3 cm2 LVEF >55%

3 years

80% at 3 years

Minners et al. 201319

Prospective

Vmax 3–4 m/s

948

68 ± 9.7

3.8 ± 1.2 years

95.7% at 1 year 68.5% at 3 years 49.1% at 5 years

Yechoor et al. 201320

Retrospective

Vmax 3–4 m/s MG 25–40 mmHg AVA 1.0–1.5 cm2 EF 49 ± 12%

104

74 ± 10

22 months

48% at 1 year 24% at 3 years 15% at 5 years

Delsalle et al. 201921

Prospective

AVA 1.0–1.5 cm2

508

75 ± 11

13.6% NYHA III or IV

47 months

53% survival at 6 years

Lancellotti et al. 201822

Retrospective

AVA 1.0–1.5cm2

514

68 ± 13

2.3 years

94% survival at 2 years 89% at 4 years

Van Gils et al. 201727

Retrospective

Vmax 2–4 m/s AVA 1.0–1.5 cm2 LVEF <50%

305

73 ± 11

76% 638 days (IQR 34% NYHA III–IV 280–1137)

Samad et al. 201628

Retrospective

Vmax 3–4 m/s MG 25–39 mmHg AVA >1 cm2

1,090

75 (IQR 67–83)

5 years

Strange et al. 20195

Retrospective

Vmax 3.0–3.9 m/s MG 20.0–39.9 mmHg AVA >1 cm2

3,315

74 ± 15

1,208 days (IQR 598–2,177)

Cohort Size

39% at 4 years

21% mortality at 1 year 56% at 5 years

AS = aortic stenosis; AVA = aortic valve area; CV = cardiovascular; EF = ejection fraction; IQR = interquartile range; LVEF = left ventricular ejection fraction; MG = mean gradient; NR = not recorded; NYHA = New York Heart Association; VTI = velocity time integral.

The current data have important clinical implications. Whether they support AVR in patients with moderate AS before progression to severe is open to debate. However, it is important to question the conventional guidelines of expectantly managing these patients, suggesting that they require much closer follow-up and more aggressive management than the present guidelines indicate.

The Role of Multi-modality Imaging Echocardiography

Echocardiographic evaluation starts with a visual assessment of the structure, calcification and mobility of the valve. AS severity is conventionally graded by peak velocity, MG and AVA (Figure 1). The

classification of AS severity is not always straightforward, and echocardiographic findings are discordant in one in three patients.37 A distinction needs to be made between those with low flow (<35 ml/m2), and those with normal flow, in whom measurement inaccuracy or the discordance between a MG of 40 mmHg and a valve area of 1.0 cm2 are the more likely explanations. Additional investigations may be required. In patients with a reduced LVEF, low gradient and low AVA, dobutamine stress echocardiography may help in differentiating patients with true severe AS from pseudo-severe (moderate) AS.38 A decrease in flow may be because of an increase in global left ventricular afterload not only as a result of the valvular stenosis but also from a

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Moderate Aortic Stenosis: What is it and When Should We Intervene? Figure 1: Transthoracic Echocardiogram of Patient With Moderate Aortic Stenosis

However, LVEF may remain normal until later in the course of the disease. Systolic long axis function may be impaired, even in the presence of a normal ejection fraction, in patients with AS (Figure 1).44 Asymptomatic patients with moderate AS have subclinical impaired systolic left ventricular function as measured by peak systolic tissue velocity (S’) and strain, compared to controls (S’ 4.1 ± 1.0 versus 4.8 ± 1.1 cm/s; p<0.01 and strain −16.6 ± 2.7 versus −17.9± 2%; p<0.05). Septal E’ (early diastolic mitral annular velocity) was decreased and septal E/E’ was increased in the AS group compared with the controls.45 Patients with AS may also develop symptoms because of progressive diastolic dysfunction. A reduction in early diastolic mitral annular velocity (E’) and an increase in E/E’ were observed in patients with mild to moderate asymptomatic AS, and related to the severity of AS. These measures have been reported to correlate with left ventricular filling pressures and may be a useful predictor of developing symptoms.46 These findings demonstrate that the damage to the left ventricular myocardium is an on-going process, which starts long before the need for AVR according to the current guidelines. Impaired left ventricular GLS (LVGLS), as a potential surrogate of myocardial fibrosis, has been shown to be an independent predictor of mortality and adverse outcomes in both symptomatic and asymptomatic severe AS patients, suggesting that LVGLS is a better value for risk stratification and management of AS, than LVEF.47,48

Transthoracic echocardiogram showing normal left ventricular dimensions (A) and a calcified aortic valve (B and C). Continuous wave Doppler trace shows peak aortic velocity 3.7 m/s and mean gradient 28 mmHg (D). Left ventricular ejection fraction is 62% (3D measurement; E) and impaired global longitudinal strain (F).

decrease in systemic arterial compliance and/or increased vascular resistance.39 Assessment of the global left ventricular haemodynamic load by measuring the valvuloarterial impedance (Zva) has been shown to be superior to the standard measures of AS severity in predicting left ventricular dysfunction and clinical outcomes.40,41 Hachicha et al. have also demonstrated that Zva is a strong independent predictor of clinical outcome in patients with at least moderate AS.41 The left ventricle faces a double load; valvular and arterial, particularly in hypertension, which frequently co-exists in patients with AS. A high Zva may explain why a patient with moderate AS is symptomatic. It is currently unclear whether these patients should undergo aortic valve intervention in the presence of symptoms, even after aggressive blood pressure control.

Assessment of the Left Ventricle

There is evidence to suggest that adaptive remodelling becomes maladaptive with increasing left ventricular hypertrophy and consequent myocardial fibrosis in patients with AS. Inappropriately high left ventricular mass (iLVM) is associated with increased mortality, AVR or hospital admission.42 iLVM is also common in asymptomatic mild-to-moderate AS and is associated with reduced left ventricular contractility.43 Left ventricular impairment is a strong adverse prognostic marker and LVEF <50% even in asymptomatic patients is a Class I indication for AVR.

It has been shown that clinical outcomes of patients with moderate AS are poor, highlighting the importance of detecting even mild degrees of left ventricular dysfunction before the AS becomes severe. Zhu et al. retrospectively analysed data from 287 patients with moderate AS (aortic valve peak velocity [AVVmax] 3.2 ± 0.5 m/s, MG 24.5 ± 7.4, AVA 1.26 ± 0.14 cm2 and LVEF 62 ± 6%). They found that mortality was significantly higher in patients with GLS ≥15.2% compared with GLS ≤15.2%. LVGLS was independently associated with survival even after adjusting for age, sex, coronary artery disease, LVEF, MG and symptomatic status.49 Increased afterload could possibly be already overwhelming even if AS is only moderate among patients with impaired GLS. Patients with impaired GLS had larger left ventricular mass index with concentric left ventricular hypertrophy and lower E velocities compared to those with preserved GLS. Moderate AS based on current echocardiographic data may be associated with reduced survival, which in part may be related to comorbid clinical factors and co-existent cardiac abnormalities. Hence, the concept of staging AS and its relationship to clinical outcomes (rather than merely classifying the severity of the valve lesion based on echo criteria) may aid in the risk stratification of patients with AS. Genereux et al. characterised patients with symptomatic severe AS undergoing AVR into five stages: stage 0, no left ventricular damage; stage 1, left ventricular damage; stage 2, left atrial enlargement and mitral valve damage; stage 3, pulmonary hypertension and tricuspid damage; stage 4, right ventricular dysfunction has been proposed to aid the decision to potentially intervene in a more timely fashion. A main focus of these staging algorithms has been the changes that occur in the myocardium in AS and the pattern of left ventricular remodelling.50 Incorporation of LVGLS into the staging classification improves the prognostic value by identifying patients with more advanced cardiac damage.51 Including GLS (as a surrogate of myocardial fibrosis) in the echocardiographic evaluation of patients with AS, irrespective of its grade, may aid in the risk stratification of these patients. Early pressure unloading of the left ventricular can result in a more significant regression

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Moderate Aortic Stenosis: What is it and When Should We Intervene? of diffuse fibrosis. The limitations of the current evidence are its retrospective nature and single centre study design. There is a need for a randomised clinical trial to determine whether patients with moderate AS and impaired GLS benefit from earlier intervention.

Figure 2: Cardiac CT for Aortic Valve Assessment

Exercise Echocardiography

Exercise stress echocardiography allows not just the assessment of functional capacity and haemodynamic changes, but also the measurement of trans-valvular gradient under higher flow conditions, measurement of left ventricular contractile function and estimation of pulmonary artery systolic pressures. Little is known about how the ventricle and vasculature respond to less than severe AS and whether this could lead to symptoms in susceptible individuals. More information may be revealed about the ventricle’s adaptation/maladaptation when placed under even mild stress compared to being at rest. Moderate AS is considered a pre-symptomatic stage although there is a strong suggestion that a proportion of patients are already symptomatic; up to 60% exhibited breathlessness on exertion in one study,52 and that these symptoms on exertion are more closely linked to outcome than resting echo based severity parameters. Changes in exercise performance in patients with moderate AS are not well understood although there is evidence to support a reduction in exercise time of around 5% over 2.5year follow-up.53 A small study of 38 apparently asymptomatic patients with moderate-to-severe AS revealed symptoms were associated with a lower peak VO2 on cardiopulmonary exercise testing, and lower peak stroke index during exercise. The limitation of the current evidence is that the cohorts either contain patients with both moderate and severe AS or have incomplete exercise data. Furthermore, the exercise data are confined to relatively crude treadmill parameters such as exercise time, but they do not establish the pathogenesis of the exercise limitation. An abnormal left ventricular response to exercise (manifest by a lack of increment or decrease in LVEF on exercise) is associated with an increased likelihood of developing symptoms on exercise and lower survival free of cardiac events than those with an appropriate increase in LVEF on exercise. However, left ventricular longitudinal strain is a more powerful parameter than LVEF to predict the occurrence of symptoms, exercise tolerance and cardiac events. Huded et al., in a study of 504 asymptomatic patients with severe AS, showed that age and sex predicted metabolic equivalents (HR 1.16), LVGLS and valvuloarterial impedance, offered incremental prognostic value.54 However, at present, no clinically applicable cut offs for contractile reserve using strain in AS have been validated. Exercise stress echocardiography using tissue Doppler imaging also provides prognostic information, in mild to moderate AS. A significant increase in the E/E’ ratio during exercise predicted adverse cardiac events, beyond exercise echocardiography or exercise testing alone.55 This highlights that the increased afterload alters the ventricular filling dynamics as well as the relaxing properties of the left ventricle in AS patients. The data demonstrates that objective assessment of the myocardium and valve behaviour under stress conditions, may aid in the decision making regarding aortic valve intervention, before irreversible myocardial changes occur. Cardiopulmonary exercise testing provides an additional objective measure of exercise tolerance and has been shown to be feasible and reproducible in AS and able to identify a greater proportion of individuals with exercise intolerance than conventional parameters that are recommended in the current guidelines (symptoms or fall in blood pressure).56–58 Previous studies have shown that a significant proportion

Leaflet aortic valve Agatston calcium score of 1095 AU in a patient with moderate aortic stenosis; the blooming artefact makes the calcium appear more prominent (A). Multi-planar reconstructions of the angiographic acquisition in the short axis of the tricuspid aortic valve (B, yellow) and the respective three chamber long axis (C, blue) and respective aortic cross-cut (D, red).

of patients with apparently asymptomatic moderate-to-severe AS exhibit a peak VO2 <84% predicted.58,59 A reduced peak VO2 was associated with a lower event-free survival compared to a normal peak V02. No exercise stress echocardiography parameters however, were associated with peak V02, nor predicted event free survival.59 Whether patients with purely moderate AS exhibit exercise limitation defined by a reduced V02 peak is yet to be established.

Cardiac CT and PET

Quantification of aortic valve calcium (AVC) has been shown in multicentre studies to be reproducible and offers prognostic value above and beyond echocardiographic indices of AS severity (Figure 2).60,61 AVC load can be correlated with haemodynamic indicators of the severity of AS, as demonstrated by Boulif et al. in a study of 266 patients with moderatesevere AS (defined by an effective orifice area of <1.5 cm2), thereby potentially providing a valuable surrogate marker of AS severity.62 AVC load may predict outcome, including in asymptomatic patients, independently of other markers that may be detected on echocardiography, such as AVA and EF. The possible distortion of the former by reduction of the latter, whereby reduced LVEF may impact on the AV gradient and thereby result in functionally low AVA, renders the use of independent markers of AS severity all the more crucial in order to plan interventions of the most appropriate means and timing.63–65 The inclusion of CT-AVC in guidelines for the assessment of AS severity provides the optimal framework with which to apply this marker to clinical practice.2 A further interesting application of CT in AS is the use of hybrid PET-CT imaging to track both valvular inflammation and calcification with 18 F-flurodeoxyglucose and 18F-fluoride-PET-CT. Earlier studies have suggested that 18F-NaF activity predicts the rate of future disease progression as measured by CT-AVC and echocardiography and prospective studies are also underway to assess whether it can improve prediction of risk and response to therapy.65,66

Cardiac MRI

The importance of the transition from physiological adaptation to pathophysiological maladaptation in the myocardial remodelling response

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Moderate Aortic Stenosis: What is it and When Should We Intervene? Figure 3: Cardiac MRI in Aortic Stenosis

Valve and remodelling (A–E) and tissue characterisation (F-I). Short axis images of two patients with moderate AS. Patient one (F/H) has concentric left ventricular hypertrophy and evidence of non-infarct scarring; the LGE image (F) shows scarring of both papillary muscles as well as more subtle enhancement in the RV insertion points and subendocardially in the anterior and lateral wall; this is confirmed by elevated ECV of 35% in the same areas on the ECV map with a normal ECV of 26% in the remote myocardium (H). Patient two (G/I) has concentric LV hypertrophy; the LGE images shows diffuse, transmural late enhancement through the left ventricle with some enhancement of the right ventricle; the ECV map shows evidence of a globally severely elevated ECV of 50%, consistent with dual pathology of AS and cardiac amyloidosis. AS = aortic stenosis; ECV = extracellular volume fraction; LGE = late gadolinium enhancement; LV = left ventricle; RV = right ventricle.

in AS was highlighted over 40 years ago in pivotal work by studying myocyte hypertrophy and fibrosis on myocardial histology. Work by Schwarz and others demonstrated proportional myocyte hypertrophy and diffuse interstitial fibrosis, as well as partly disease specific patterns of fibrosis, described as compact or ‘focal’, perimyseal, perivascular, plexiform or patchy.67 In AS, interfibre and perivascular fibrosis increase disproportionally.67 Later work also demonstrated gradients of fibrosis and capillary rarefaction from the subendocardium than in the subepicardium.68,69 Fast forward, we can now identify many of these changes non-invasively by cardiac MRI (CMR) using not only the superior accuracy of CMR to quantify left and right ventricular size, hypertrophy and function (Figure 3) but also quantifying both focal scar (with late gadolinium enhancement [LGE] imaging) and diffuse fibrosis (with T1 mapping that allows the quantification of the extracellular volume fraction (ECV%). Both techniques have been validated against myocardial fibrosis on histology highlighting the previously described complex pattern of subendocardial microscars and mid-myocardial diffuse fibrosis.70–72 Importantly, focal scar can already be detected in moderate AS. Everett et al. showed both the amount of LGE and elevation of ECV% increases in moderate AS prior to left ventricular impairment or symptom onset with new scar occurring both at the sites of existing LGE and, in a quarter of

patients, at remote sites with the development of new areas of non-infarct LGE.73 Both LGE and ECV% are independent predictors of outcomes after AVR, but importantly LGE is irreversible, whereas diffuse fibrosis quantified by ECV% regresses after AVR.74–77 Whether myocardial scar can be used to guide early AVR in asymptomatic severe AS, is currently under investigation in the EVOLVED study, which is the first multicentre randomised controlled trial to compare early AVR to routine care in asymptomatic severe AS guided by the presence of focal scar on LGE imaging.78 If this study provides a role of CMR in guiding timing of intervention, then the next conceivably are of CMR-guided early intervention will be moderate AS with evidence of myocardial decompensation (Figure 4). The increased use of CMR has also highlighted dual pathology AS and transthyretin-type cardiac amyloidosis, which occurs in one in eight elderly patients referred for TAVR.78,79 Although TAVR is beneficial in AS-amyloidosis, diagnosis is still important because new amyloid-directed pharmacotherapies are now available and should be considered. Beyond fibrosis and infiltration, CMR can also detect myocardial perfusion reserve and oedema, with studies on-going to establish the importance of microvascular perfusion and low grade of inflammation in the pathophysiological remodelling of AS.

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Moderate Aortic Stenosis: What is it and When Should We Intervene?

Valve Stenosis

Figure 4: Imaging Parameters in Aortic Stenosis Asymptomatic

Diastolic

Symptoms

Early AVR

Recovery

AVR Severe AS

Moderate AS

LVEF

Conclusion

LVH

Focal Scar Time Concept figure illustrating Imaging parameters in the natural history of AS. AS = aortic stenosis; AVR = aortic valve replacement; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy.

Just a Question of Classification?

The ultimate question is whether we need to re-classify AS bearing in mind the importance of the myocardial response and its impact on outcome, and the improved outcomes with better surgical and transcatheter technology (that lower the upfront risk and change the balance of risk-versus-benefit). While the label ‘severe’ signals the need for intervention, we should aim to describe the valvular insult to the myocardium and upstream cardiac structures as significant or nonsignificant and then assess the resultant response. How classification can have a counterproductive effect can be seen by the strict interpretation of the European Society of Cardiology (ESC) 2017 guidelines that reclassified low-gradient severe AS to moderate AS unless presenting with low flow status (stroke volume index ≤35 ml/m2) and high calcium scores (emphasising on mean pressure gradient and an integrated approach). Chan et al. demonstrated that 1.

Bohbot Y, Rusinaru D, Delpierre Q, et al. Risk stratification of severe aortic stenosis with preserved left ventricular ejection fraction using peak aortic jet velocity: an outcome study. Circ Cardiovasc Imaging 2017;10:e006760. https://doi. org/10.1161/CIRCIMAGING.117.006760; PMID: 29021260. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38:2739-2791. https://doi.org/10.1093/ eurheartj/ehx391; PMID: 28886619. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline on the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2021;77:e25–e197. https://doi.org/10.1016/j.jacc.2020.11.018; PMID: 33342586. Musa TA, Treibel TA, Vassilliou VS, et al. Myocardial scar and mortality in severe aortic stenosis. Circulation 2018;138:1935–47 https://doi.org/10.1161/ CIRCULATIONAHA.117.032839; PMID: 30002099. Strange G, Stewart S, Celermager D, et al. Poor long term survival in patients with moderate aortic stenosis. J Am Coll Cardiol 2019 74:1851–63. https://doi.org/10.1016/j. jacc.2019.08.004; PMID: 31491546. Dweck MR, Boon NA, Newby DE, et al. Calcific aortic stenosis: a disease of the valve and myocardium. J Am Coll Cardiol 2012;60:1854–63. https://doi.org/10.1016/j. jacc.2012.02.093; PMID: 23062541. Treibel TA, Kozor R, Fontana M, et al. Sex dimorphism in the myocardial response to aortic stenosis. JACC Cardiovasc Imaging 2018;11:962–73 https://doi.org/10.1016/j.

strict adherence to 2017 ESC guidelines for valvular heart disease reclassified 45% of their severe asymptomatic severe AS cohort to moderate (PRIMID-AS) and that both the severe and reclassified groups had a higher risk compared with moderate AS with the reclassified group demonstrating an intermediate risk.80 This work from the PRIMID-AS investigators demonstrates that moderate AS clearly is in grey area where exercise testing, multimodality imaging, and possibly lower AS severity cut-offs may personalise the treatment of AS and may improve risk stratification. Moderate AS carries a high morbidity and mortality and there is evidence to suggest that these patients may benefit from earlier intervention. The current evidence highlights the importance of careful surveillance of these patients. However, small patient numbers and the retrospective study nature limit much of the evidence. Echocardiography is pivotal in guiding management, although alternative imaging modalities such as CT, CMR and PET are increasingly being used to assess disease activity and progression. A new era of randomised clinical trials is required to evaluate the hypothesis that imaging-driven care in earlier stage aortic valve disease with upstream intervention would result in better long-term clinical outcomes.

Clinical Perspective

• Aortic stenosis is the most common left-sided valve lesion

requiring intervention and carries a substantial morbidity and mortality burden. • Clear guidelines exist for the management of patients with symptomatic severe aortic stenosis. • However, patients with moderate aortic stenosis may also experience symptoms, to which no other cause can be attributed to other than the valve. • It is well recognised that aortic stenosis is not only a disease of the valve, but also of the myocardium, and that a significant proportion of patients with moderate aortic stenosis will also have left ventricular dysfunction.

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Expert Opinion

What an Interventionalist Needs to Know About MI with Non-obstructive Coronary Arteries Robert Sykes ,1,2 Daniel Doherty ,1 Kenneth Mangion ,1,2,3 Andrew Morrow

1,2

and Colin Berry

1,2,3

1. West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Glasgow, UK; 2. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK; 3. Department of Cardiology, Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde Health Board, Glasgow, UK

Abstract

MI with non-obstructive coronary arteries (MINOCA) is caused by a heterogeneous group of vascular or myocardial disorders. MINOCA occurs in 5–15% of patients presenting with acute ST-segment elevation MI or non-ST segment elevation MI and prognosis is impaired. The diagnosis of MINOCA is made during coronary angiography following acute MI, where there is no stenosis ≥50% present in an infarct-related epicardial artery and no overt systemic aetiology for the presentation. Accurate diagnosis and subsequent management require the appropriate utilisation of intravascular imaging, coronary function testing and subsequent imaging to assess for myocardial disorders without coronary involvement. Although plaque-related MINOCA is currently managed with empirical secondary prevention strategies, there remains an unmet therapeutic need for targeted and evidence-based therapy for MINOCA patients and increased awareness of the recommended diagnostic pathway.

Keywords

MINOCA, acute coronary syndrome, MI, interventional cardiology, non-obstructive coronary artery disease Disclosure: CB is employed by the University of Glasgow, which holds consultancy and research agreements for his work with companies that have commercial interests in the diagnosis and treatment of angina, including Abbott Vascular, AstraZeneca, Boehringer Ingelheim, GSK, HeartFlow, Menarini, Novartis and Siemens Healthcare. CB is supported by research funding from the British Heart Foundation (PG/17/2532884, RE/13/5/30177, RE/18/6/34217). All other authors have no conflicts of interest to declare. Received: 4 March 2021 Accepted: 26 April 2021 Citation: Interventional Cardiology Review 2021;16:e10. DOI: https://doi.org/10.15420/icr.2021.10 Correspondence: Colin Berry, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK. E: colin.berry@glasgow.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

MI with non-obstructive coronary arteries (MINOCA) is a heterogeneous group of vascular or myocardial disorders that was first reported over 80 years ago.1 MINOCA is not a benign diagnosis, with outcomes similar to those of patients with acute MI and obstructive coronary disease up to 1 year (12-month mortality 0.6% versus 2.3%, respectively; p=0.68).2,3 MINOCA occurs in 5–15% of patients presenting with acute ST-segment elevation MI (STEMI) or non-ST segment elevation MI (NSTEMI), depending on the observed population and definition used.4,5 Compared with obstructive coronary artery disease, factors associated with MINOCA include female sex, younger age (<55 years), genetics and physiological stress.6–8 Accurate diagnosis and subsequent management require the appropriate utilisation of intravascular imaging and coronary function testing, in addition to echocardiographic and cardiac MRI (CMR) to assess for the presence of infarction or myocardial disorders without coronary involvement. It is important to reach a definitive diagnosis because MINOCA patients have impaired survival rate compared with age- and sex-matched healthy individuals.3,9–11

MI, a working diagnosis is made during angiography in the absence of culprit obstructive coronary artery disease (epicardial coronary artery stenosis ≥50%) or an apparent systemic cause for the presentation.12,13 Approximately one-third of patients have been reported to present with suspected STEMI within an emergency setting and the remaining majority as NSTEMI patients undergoing subsequent angiography.14

Definition and Pathophysiology of MINOCA

Diagnosis and Evaluation of Patients with MINOCA

The diagnosis of MINOCA is dependent on the presence of clinical acute MI and the absence of obstructive coronary disease. In a patient presenting with symptoms of ischaemia, cardiac enzyme elevation and echocardiographic or electrocardiographic features suggestive of acute

This working diagnosis then requires further investigation to establish the underlying pathophysiology for the presentation and prevent inadequate or inappropriate therapeutic strategies. MINOCA disorders can be classified within the fourth universal definition of MI.15 They may meet criteria for type 1 MI, where epicardial coronary artery disorders are diagnosed, or type 2 MI due to endothelial dysfunction or oxygen supply and demand mismatch, or myocardial injury. Examples of underlying diagnoses in patients with a working diagnosis of MINOCA are summarised in Table 1. Where a patient meets the criteria for a working diagnosis of MINOCA (universal acute MI criteria, infarct-related epicardial stenosis ≤50%, absence of overt alternative systemic cause) during angiography, then further invasive and adjunctive investigations should be considered at this

What an Interventionalist Needs to Know About MINOCA Table 1: Classification of Underlying Diagnoses in Patients Presenting with MINOCA Aetiology

Underlying Diagnosis

Epicardial coronary artery disorder

Atherosclerotic plaque rupture, ulceration, fissuring or erosion with non-obstructive or no coronary artery disease Coronary artery dissection or aortic dissection with coronary extension with non-obstructive or no coronary artery disease

Oxygen supply–demand mismatch

Coronary artery vasospasm Coronary artery embolism Anaemia Tachyarrhythmias or bradyarrhythmias Hypotension or hypertension Severe aortic valve disease Respiratory failure

Endothelial dysfunction

Coronary microvascular dysfunction or spasm

Other*

Myocarditis with or without pericarditis Pulmonary embolism Heart failure Other systemic condition (e.g. sepsis)

*Other causes may be diagnosed following further investigation and should be considered separately because they are typically associated with myocardial injury and not considered an MI within the fourth universal definition of MI. This is an important indication for cardiac MRI within the suspected MINOCA patient. MINOCA = MI with non-obstructive coronary arteries.

Figure 1: Angiography of MINOCA

point (Figures 1 and 2).13 Coronary intravascular ultrasound (IVUS) or optical coherence tomography (OCT) enables the operator to assess for ‘missed’ obstructive disease or dissection in addition to causes of type 1 MINOCA (plaque rupture, erosion, ulceration, intraplaque haemorrhage). Atherosclerotic plaque disruption has been identified using IVUS in approximately 40% of cases of MINOCA.16,17 Reynolds et al. visualised plaque rupture, intraplaque cavity or layered plaque using OCT in 46% of women enrolled in a recent study (STEMI at presentation in 3.5%) and OCT combined with CMR identified the underlying MINOCA diagnosis in 85% of included patients (64% ischaemic aetiology).18 However, while providing insights into MINOCA patients with atherosclerosis, a limitation of that study was that enrolment was limited to 14% (170/1,173) of eligible patients, and so the results may not be representative of all patients with MINOCA.

A: Normal epicardial arteries; B: Plaque rupture on optical coherence tomography (arrows); C: Coronary dissection on intravascular ultrasound (arrows); D: Coronary vasospastic response to acetylcholine (arrows); E: Iintracoronary physiology demonstrating an increased index of microvascular resistance (arrow). MINOCA = MI with non-obstructive coronary arteries.

Further invasive investigations include coronary pressure wire to assess for coronary microvascular dysfunction and vasospasticity. These should be considered once intracoronary imaging has ruled out coronary dissection or plaque disruption or rupture. In order to evaluate for microvascular and vasospastic abnormalities, coronary flow reserve (CFR; abnormal <2.0) should be measured and the index of microcirculatory resistance (IMR; abnormal ≥25) calculated. Fractional flow reserve is not valid in culprit coronary arteries and may be useful for the evaluation of non-culprit coronary artery disease. In the absence of results suggesting microvascular disease (e.g. normal CFR and IMR) and no epicardial stenosis, vasospasticity can be assessed using acetylcholine testing to investigate for epicardial or microvascular vasospasm. Left ventriculography may also be of value in the assessment of other causes, such as takotsubo syndrome, and is routinely performed in many percutaneous coronary intervention (PCI) centres in addition to measurement of left ventricular end-diastolic pressure (LVEDP). Ventriculography may also indicate an epicardial territorial distribution of impaired kinesis implicating a single epicardial artery, compared with a microvascular pattern involving an extended territory of one or more arteries. The upper limit of normal for LVEDP is 10 mmHg, and LVEDP >18 mmHg is associated with an adverse post-MI prognosis.19

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What an Interventionalist Needs to Know About MINOCA

Ischaemic presentation Symptoms of ischaemia Elevated cardiac enzymes Electrocardiographic features of ischaemia Echocardiographic evidence of ischaemia

Consider alternative systemic diagnosis (e.g. sepsis)

Type 2 MI or myocardial injury

Invasive coronary angiography

Obstructive coronary disease

Type 1 MI

Alternative systemic diagnosis (e.g. pulmonary embolism)

Type 2 MI or myocardial injury

Culprit artery – no obstructive disease

MINOCA

Review for ‘missed’ angiographic diagnosis, e.g. coronary dissection

Consider IVUS/OCT intracoronary imaging and pressure-wire (CFR/IMR) assessment with acetylcholine and left ventriculography

Laboratory sampling (serial cTnI, CRP, U&Es, FBC, NT-proBNP, D-dimer)

Evidence of ischaemic event

Takotsubo

Acute phase non-invasive imaging (echocardiogram, cardiac MRI, CT)

Microvascular dysfunction or vasospasm Unclassified MINOCA

Cardiomyopathy

Myocarditis Plaque rupture

Guideline-directed management and serial non-invasive imaging if impaired cardiac function

Figure 2: Diagnostic Pathway for MINOCA

Plaque erosion

CFR = coronary flow reserve; CRP = C-reactive protein; cTnI = cardiac troponin I; FBC = full blood count; IMR = index of microcirculatory resistance; IVUS = intravascular ultrasound; MINOCA = MI with non-obstructive coronary arteries; NT-proBNP = N-terminal pro B-type natriuretic peptide; OCT = optical coherence tomography; U&Es = urea and electrolytes.

Periprocedural laboratory investigations in patients with MINOCA should include relevant biochemical and haematological tests (i.e. serial cardiac troponin measurement, N-terminal pro B-type natriuretic peptide, coagulation screen and haemostasis, D-dimer, full blood count, renal function, electrolytes, glucose and C-reactive protein). If an underlying infection is suspected, serum cultures should be obtained and screening for viral (e.g. SARS-CoV-2 infection) and additional bacterial sources considered. Following invasive angiography, transthoracic echocardiography should be performed specifically assessing for the presence of regional wall motion abnormalities, embolic sources, pericardial effusion and typical features of takotsubo syndrome. Further echocardiographic assessment for patent foramen ovale and atrial septal defect as embolic sources may be considered using transoesophageal or bubble contrast echocardiography. Cross-sectional CT should be performed where other causes are suspected (e.g. SARS-CoV-2 infection, pulmonary embolism or aortic dissection). CT coronary angiography is not guideline indicated, but may be of value where intravascular imaging has not been performed during angiography and diagnostic uncertainty remains to assess for intramural haematoma, dissection and the burden coronary plaque disease. CMR can identify inflammation, oedema and scar and can assess myocardial function by T1- and T2-weighted imaging. CMR is an important

diagnostic tool and is guideline recommended in all patients with MINOCA.12 If present on CMR, late gadolinium enhancement localises the site of myocardial damage, and the pattern of distribution suggests the diagnosis (Figure 3). Subendocardial or transmural enhancement is typically of an ischaemic aetiology or hypereosinophilic syndrome. Subepicardial enhancement may be observed in myocarditis, cardiac sarcoid or cardiomyopathy associated with Duchenne muscular dystrophy. Mid-wall enhancement is associated with dilated cardiomyopathy, hypertrophic cardiomyopathy, Duchenne muscular dystrophy, Becker’s muscular dystrophy, Anderson–Fabry disease, sarcoidosis or myocarditis. Finally, global endocardial enhancement is associated with amyloidosis, systemic sclerosis, hypereosinophilic syndrome or Churg–Strauss syndrome, whereas the absence of late gadolinium enhancement may be in keeping with microvascular dysfunction or a non-cardiac cause of the presentation. CMR should be performed as soon as feasible after identification of MINOCA. However, there may be logistical issues with performing CMR in the acute setting (e.g. accessibility of CMR) and it is therefore often performed during the convalescent phase of the illness. This limits the diagnostic yield and certainty of the underlying diagnosis, limiting the potential for acute and appropriate pharmacological intervention.

Therapeutic Strategies for Patients with MINOCA

The treatment of MINOCA requires an individualised approach depending on the underlying diagnosis and may be limited by clinicians’ access to

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What an Interventionalist Needs to Know About MINOCA Figure 3: MINOCA and Cardiac MRI

instrumental in the pathogenesis of plaque disruption in MINOCA and statin therapy improves plaque stability even in minimal atherosclerotic disease. Patients with coronary artery dissection should receive aspirin and β-blockers, with additional antiplatelet agents (e.g. clopidogrel) and ACEi/ARB or statins considered. Coronary embolism and MINOCA may be transient and therefore a diagnostic challenge. Where it is the established diagnosis, treatment of the hypercoagulable state (e.g. diabetic ketoacidosis, heparin-induced thrombocytopenia) in addition to antiplatelet (or anticoagulation where an embolic source is identified), ACE/ARB and statin is appropriate. MINOCA patients with an underlying diagnosis of epicardial or microvascular vasospasm should receive calcium channel blockers, although nitrates and potassium channel activators may be considered as adjuncts in addition to ACEi/ARB treatment after MI, and statin therapy may be considered if coronary atherosclerosis is identified. Patients with structural microvascular disease should receive anti-anginal therapy in addition to treatment with ACEi/ARB following MI and statin. Microvascular disease is often under- or untreated, and effective treatment may benefit from a stratified approach with trials for novel therapeutic options awaited.24,25

A, B: Images from a patient with limited MI. There is subendocardial late gadolinium enhancement (LGE) within the basal to mid-lateral wall (yellow arrows) in the short (A) and horizontal long (B) axis views. C, D: Images from a patient with acute myocarditis. There is an area of increased T2-weighted signal intensity (C; black arrow) in the basal anteroseptum suggestive of myocardial oedema that colocalises with an area of extensive LGE (D; yellow arrow). MINOCA = MI with non-obstructive coronary arteries.

CMR within PCI centres or the use of CMR as a diagnostic adjunct. There remains a paucity of randomised control trial data on treatment in MINOCA, although observational and registry studies have reported lower mortality in MINOCA patients who received renin–angiotensin– aldosterone system (RAAS) inhibitors and statins, including a propensity score-matched analysis of 9,138 patients with MINOCA within the SWEDEHEART registry.20,21 The results indicate long-term beneficial effects of treatment with statins and angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) on outcomes in patients with MINOCA, a trend towards a positive effect of β-blocker treatment and a neutral effect of dual antiplatelet therapy.20,21 MINOCA-BAT (NCT03686696) is a randomised trial of a β-blocker and ACEi or ARB versus placebo involving 3,500 MINOCA patients. The primary outcome of MINOCA-BAT is mortality or readmission due to MI, stroke or heart failure, and the trial is due to complete in 2025. The results of that study may affect future treatment guidelines for patients with MINOCA.22 Mineralocorticoid receptor antagonists (MRA) may have a theoretical role in improving outcomes of MINOCA patients because aldosterone levels immediately after acute MI are associated with all-cause mortality. Aldosterone mediates the downstream effects of RAAS activation, including endothelial dysfunction, inflammation and fibrosis, but, at present, there are no trial data of MRA therapy in MINOCA patients.23 While we wait for trial evidence, it is currently recommended that patients with MINOCA secondary to plaque disruption or with evidence of ischaemic damage on CMR receive dual antiplatelet therapy (12 months followed by lifelong single agent), high-dose statin (including in patients with minimal plaque burden), β-blocker and ACEi or ARB.12 The rationale for this is comparable to that for obstructive coronary artery disease, because thrombosis and/or thromboembolism are thought to be

Treatment for diagnoses of supply–demand mismatch depends on the underlying cause, although additional secondary prevention may be indicated in the presence of mild or non-culprit coronary artery disease.

Outcomes of Patients with MINOCA

MINOCA is frequently collated into a single entity within observational studies, but the prognosis and outcomes of patients depend on the underlying diagnosis for their presentation. Mortality and the incidence of major adverse cardiac events (MACE) for MINOCA patients are reported as comparable with those of patients with obstructive coronary artery disease, and significantly worse than for the general population.3,21 Within the SWEDEHEART registry, approximately one in four patients experience a MACE within 4 years, including death, recurrent MI, hospitalisation with heart failure or ischaemic stroke.26 Although that registry does not use current European Society of Cardiology MINOCA criteria and should therefore be interpreted with caution, a large systematic review and meta-analysis of 1,924 MINOCA patients reported that all-cause mortality at 12 months was 4.7% (SWEDEHEART mortality 2.4% at 6 months).2,14 This reflects an unmet clinical need for effective preventative therapy in this patient group, which is typically younger with fewer comorbidities than patients with obstructive coronary artery disease.14 Risk stratification is challenging in patients with MINOCA where the inciting aetiology is uncertain. However, increased severity of atherosclerosis and elevated serum C-reactive protein are associated with impaired prognosis and are quantifiable during routine assessment.2 Atherosclerotic plaque rupture and related local or systemic inflammation are associated with an increased risk of recurrent events compared with plaques with an intact fibrous cap or lack of objective inflammation (e.g. identified with OCT or IVUS during angiography or subsequently on MRI in addition to serum inflammatory markers).27 These techniques may therefore aid in prognostic stratification, and recent evidence suggests a potential prognostic role for coronary CT

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What an Interventionalist Needs to Know About MINOCA angiography with the assessment of pericoronary fat index (pFAI). Higher pFAI values and an increased prevalence of higher-risk non-obstructive intracoronary plaques have been observed in MINOCA patients compared with controls with non-obstructive coronary disease.28 Although there are no studies focused on the effects of MINOCA on quality of life, including persistent ischaemic symptoms and psychosocial parameters, the CorMicA trial demonstrated that, in patients with angina symptoms and/or signs of ischaemia with no obstructive coronary artery disease, diagnostic certainty and appropriate stratification of medical therapy can improve both symptoms of ischaemia and quality-of-life scoring.24 MINOCA-BAT will include a substudy assessing the prevalence of angina pectoris in addition to health-related quality of life, anxiety, depression and psychiatric comorbidities.22

Conclusion

MINOCA is a heterogeneous working diagnosis that requires a multimodal approach to investigation, both during angiography and subsequently with CMR. Identification of the underlying cause is paramount, although, based on observational data, approximately two-thirds of cases may be related to plaque disruption. Although treatment is currently empirical 1.

10.

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Clinical Perspective

• MI with non-obstructive coronary arteries (MINOCA) is a • • • • •

heterogeneous working diagnosis requiring further investigation during and after invasive angiography. Clinicians should consider the use of intracoronary imaging and coronary physiology testing during angiography to assess for plaque disruption and vasospasticity. Cardiac MRI with gadolinium contrast is recommended in all MINOCA patients. MINOCA is not benign and has comparable outcomes with acute MI due to obstructive coronary artery disease. Treatment of the underlying cause is paramount although, at present, often empirical. There is an unmet clinical need for stratified therapy for patients with MINOCA.

acute coronary syndrome without obstructive coronary artery disease. Eur Heart J 2018;39:102–10. https://doi. org/10.1093/eurheartj/ehx491; PMID: 29029035. Larsen AI, Galbraith PD, Ghali WA, et al. Characteristics and outcomes of patients with acute myocardial infarction and angiographically normal coronary arteries. Am J Cardiol 2005;95:261–3. https://doi.org/10.1016/j. amjcard.2004.09.014; PMID: 15642564. Collet JP, Thiele H, Barbato E, et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021;42:1289–367. https://doi.org/10.1093/eurheartj/ ehaa575; PMID: 32860058. Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the Management of Acute Myocardial Infarction in Patients Presenting with ST-segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–77. https://doi.org/10.1093/eurheartj/ehx393; PMID: 28886621. Pasupathy S, Air T, Dreyer RP, et al. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation 2015;131:861–70. https://doi.org/10.1161/ CIRCULATIONAHA.114.011201; PMID: 25587100. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction. Eur Heart J 2019;40:237– 69. https://doi.org/10.1093/eurheartj/ehy462. Reynolds HR, Srichai MB, Iqbal SN, et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation 2011;124:1414–25. https://doi.org/10.1161/ CIRCULATIONAHA.111.026542; PMID: 21900087. Ouldzein H, Elbaz M, Roncalli J, et al. Plaque rupture and morphological characteristics of the culprit lesion in acute coronary syndromes without significant angiographic lesion: analysis by intravascular ultrasound. Ann Cardiol Angeiol (Paris) 2012;61:20–6. https://doi.org/10.1016/j. ancard.2011.07.011; PMID: 21903196. Reynolds HR, Maehara A, Kwong RY, et al. Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of myocardial infarction with nonobstructive coronary arteries in women. Circulation 2021;143:624–40. https://doi.org/10.1161/ CIRCULATIONAHA.120.052008; PMID: 33191769. Maznyczka AM, McCartney PJ, Oldroyd KG, et al. Risk stratification guided by the index of microcirculatory resistance and left ventricular end-diastolic pressure in

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Structural

Haemodynamic Interplay Between Concomitant Left Ventricular Outflow Tract Obstruction and Aortic Stenosis Priya Bansal ,1 Hamza Lodhi ,1 Adithya Mathews ,1 Anand Desai,1 Ramez Morcos ,1 Brijeshwar Maini 1,2 and Houman Khalili 1,2 1. Department of Cardiovascular Diseases, Florida Atlantic University, Boca Raton, FL, US; 2. Tenet Healthcare Corporation, Boca Raton, FL, US

Abstract

The authors describe a patient with hypertrophic cardiomyopathy with concomitant left ventricular outflow tract obstruction and aortic stenosis. Detailed haemodynamic assessment of the serial lesions was performed. Alcohol septal ablation resulted in a significant reduction of gradients across the left ventricular outflow tract.

Keywords

Structural heart disease, cardiology, alcohol septal ablation, haemodynamic analysis Disclosure: The authors have no conflicts of interest to declare Received: 29 December 2020 Accepted: 29 March 2021 Citation: Interventional Cardiology Review 2021;16:e11. DOI: https://doi.org/10.15420/icr.2020.36 Correspondence: Houman Khalili, Florida Atlantic University, Tenet Florida, Boca Raton, FL 33431, US. E: houman.khalili@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Concomitant aortic stenosis (AS) and left ventricular outflow tract (LVOT) obstruction are increasingly encountered in clinical practice given the ageing population. The haemodynamic interplay between these two diseases can be challenging to diagnose, discern and treat. Investigating these patients may require invasive haemodynamic assessment to determine not only the contribution of each to the totality of the obstructive physiology, but also their effect on one another. Nonetheless, identifying obstructive lesions in series may still be difficult, like interpreting fractional flow reserve in serial coronary stenoses.1 LVOT obstruction can be masked because of the increased afterload in severe AS, while severe LVOT obstruction can decrease stroke volume leading to a low-gradient, low-flow AS. The most definitive process is assessment of the residual gradient after treatment of the most obstructive lesion as determined by pullback.

Case Report

An 82-year-old man with a history of hypertension and AS was referred to our structural heart clinic for evaluation of transcatheter aortic valve replacement. He had New York Heart Association class III heart failure symptoms and was feeling lightheaded. His cardiac examination was notable for a laterally displaced apical impulse and a harsh 3/6 latepeaking systolic murmur with no significant change apparent when standing or during the Valsalva manoeuvre. An outpatient transthoracic echocardiogram (TTE) report indicated severe AS with a mean gradient (MG) of 47 mmHg and aortic valve area (AVA) of 0.8 cm2 by continuity. Cardiac multidetector CT (MDCT) revealed non-obstructive coronary artery disease; there was asymmetric septal hypertrophy and systolic anterior motion (SAM) of

the mitral leaflet, which raised concerns about concomitant LVOT obstruction. Repeat TTE performed at our institution revealed hypertrophy of the basal septum associated with SAM and flow acceleration at the LVOT (Supplementary Video 1). Pulsed-wave Doppler at the level of LVOT revealed a late-peaking, dagger-shaped spectral envelope with aliasing consistent with LVOT obstruction (Figure 1). The peak instantaneous gradient (PG) was 56 mmHg at rest (Figure 2). The aortic valve was calcified with reduced excursion. A baseline heart rate of 50–55 BPM and concomitant aortic stenosis limited additional medical therapy options. Given the patient’s advanced age and comorbidities, the multidisciplinary decision was made to carry out detailed haemodynamic assessment of LVOT obstruction and aortic stenosis with possible alcohol septal ablation (ASA). Baseline simultaneous ascending aortic (AAo) and left ventricular (LV) pressure tracings were obtained using a pigtail catheter and an end-hole multipurpose (MP) catheter, respectively. AAo pressure tracing exhibited the spike-and-dome pattern after premature ventricular contraction (PVC) – associated with dynamic LVOT obstruction – with a combined LVOT/AS peak-to-peak (PP) gradient of 75 mmHg at rest. AAo pulse pressure decreased after PVC provocation (the Brockenbrough–Braunwald– Morrow sign), with an increase in the combined gradient to 140 mmHg. The MP catheter was carefully withdrawn to below the aortic valve to isolate the gradient across the valve, and simultaneous pressures were re-obtained. The AAo-subaortic PP gradient measured 24 mmHg at rest, with no significant change after PVC (Figures 3 and 4). Given the findings of severe dynamic LVOT obstruction in the absence of significant mitral valve regurgitation, ASA was then pursued. The most

Haemodynamic Interplay Between Concomitant LV Outflow Tract Obstruction and Aortic Stenosis Figure 1: Pulsed-wave Doppler A

Pulsed-wave Doppler used to scan from the level of the of the left ventricular outflow tract (LVOT) to the apex to identify the maximal point of flow. A: Doppler tracing at the level of the apex. B: Characteristic lobster-claw Doppler tracing at the level of mitral valve-septal contact. C: Aliasing at the level of the LVOT with a late-peaking, dagger-shaped spectral envelope.

Figure 2: Continuous-wave Doppler at the Left Ventricular Outflow Tract

Repeat invasive AAo/LV pressure tracings were obtained. AAo pressure tracing now exhibited a delayed upstroke pattern at rest and after PVC – consistent with aortic stenosis – and a reduced resting combined LVOT/ AS PP gradient of 30 mmHg (Figure 5). The AAo pulse-pressure remained unchanged after PVC provocation with a mild increase in PP gradient to 50 mmHg, consistent with the fixed stenosis of AS. Immediately after ASA, LVOT PG measured 9 mmHg by Doppler. The patient remained haemodynamically stable with close monitoring in the intensive care unit for 48 hours. No conduction abnormalities were noted on telemetry. He was discharged home and, 6 weeks after the procedure, LVOT PG measured 9 mmHg by Doppler. Aortic valve MG measured 27 mmHg and AVA 1.2 cm2 by the continuity equation. Given the complete resolution of his symptoms, watchful waiting was opted for his AS.

Continuous-wave Doppler tracing at the level of the left ventricular outflow tract and aortic valve shows peak instantaneous gradient of 56 mmHg at rest.

Figure 3: Simultaneous Ascending Aorta and Left Ventricular Pressures

Discussion

Serial lesions, such as those found in hypertrophic obstructive cardiomyopathy (HOCM) and AS, negate modelling assumptions made with the modified Bernoulli equation on echocardiography, because the proximal stenosis results in a significant velocity approaching the distal stenosis. Viscosity and friction may also be more relevant with tandem lesions, which the modified Bernoulli equation does not account for.3 Careful interdisciplinary pre-procedural planning with multi-modality imaging is essential before concomitant structural diseases are assessed. Although cardiac MDCT can be used to assess the LVOT diameter and the morphological manifestation of SAM, it provides less information about haemodynamics and tissue characterisation than cardiac MRI.4 Therefore, invasive haemodynamic measurements are essential.

Aortic pressure tracing demonstrates a spike and dome pattern after premature ventricular contraction. Peak-to-peak gradient measures 75 mmHg at rest, and 140 mmHg after premature ventricular contraction with a paradoxical reduction in pulse pressure (the Brockenbrough– Braunwald–Morrow sign).

basal septal perforator, a branch of the ramus intermedius artery, was selected as the initial target. ASA was performed in the usual fashion (Supplementary Video 2).2

Patients with AS demonstrate a parvus et tardus tracing – reduced in amplitude and delayed – because of the restrictive opening of the valve and the resulting fixed obstruction. LVOT obstruction, on the other hand, is dynamic, occurring in late systole with aortic pressure rising rapidly at the time of aortic valve opening, thus creating a spike-and-dome pattern. Typically, after a PVC, there is a compensatory pause that causes an increase in the diastolic filling time and subsequently expands the diastolic volume. Following the Frank-Starling mechanisms, the stroke volume increases with end-diastolic volume expansion, resulting in more cardiac muscle stretch and myocardial contractility, causing a rise in the arterial pulse pressure.5 The Brockenbrough–Braunwald–Morrow phenomenon occurs with LVOT obstruction as a paradoxical decline in

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Haemodynamic Interplay Between Concomitant LV Outflow Tract Obstruction and Aortic Stenosis Figure 5: Simultaneous Ascending Aorta and Left Ventricular Pressures after Alcohol Septal Ablation

Aortic pressure tracing demonstrates a delayed upstroke pattern. The peak-to-peak gradient measures 30 mmHg at rest and increases to 50 mmHg after premature ventricular contraction, with no significant change in pulse pressure or waveform.

arterial pulse pressure after a PVC. However, with both disease processes coexisting, the decline in pulse pressure may be blunted.6

Figure 4: Simultaneous Ascending Aortic and Subaortic Pressures

In the presented case, the overall haemodynamic findings were consistent with a large contribution from the LVOT to the overall obstruction: a spikeand-dome pattern; a post-PVC drop in aortic pulse pressure; and a higher trans-LVOT gradient relative to trans-AS gradient. Alternatively, pharmacological agents, such as phenylephrine, can be used to induce afterload augmentation, reducing outflow obstruction.7 LVOT obstruction may be relieved first, not only to help accurately determine the severity of AS but also to reduce the risk of haemodynamic derangement after aortic valve replacement. With concomitant severe AS and LVOT obstruction, aortic valve replacement relieves the high afterload, which can worsen the degree of LVOT obstruction because of increased flow drags and Bernoulli force. ASA emerged in the mid-1990s and has since developed as a safe alternative to surgical myectomy for treating elderly patients with significant comorbidities and a favourable coronary anatomy whose symptoms are refractory to optimal medical therapy.8 Left anterior descending artery dissection, coronary artery spasm, anterior wall infarction and cardiac perforation are possible complications (2%), while atrioventricular block is the most common.9,10 ASA may cause a transient or permanent disruption of the conduction system: first-degree atrioventricular block can develop in 53% of patients, right bundle branch block in 46% and complete heart block requiring permanent pacemaker implantation in 10.5%.11,12 A slower rate of alcohol injection has been correlated with a lower incidence of complete heart block.12 Additionally, the overall incidence of complications has been correlated with decreasing alcohol dose (from a mean of 2.9 ml to 0.8 ml).13 There is also the potential for an arrhythmogenic scar to develop but this has not been demonstrated to have a deleterious impact on long-term survival.14

The peak-to-peak gradient measures 24 mmHg and the mean gradient measures 21 mmHg. No significant increase in post-premature ventricular contraction beat gradient (asterisk).

After the procedure, most of the acute reduction in gradient likely represents stunning and is pathophysiologically different from the more delayed phenomenon, which is a result of scarring and thinning of the basal septum. The immediate diminution in the outflow gradient may be followed by a recurrence of the gradient 1–3 days after ASA. Therefore, it is recommended to repeat TTE with assessments of LVOT and AS gradients 1–2 months later, at which time decision for AS treatment can be made.15

Conclusion

The presented case illustrates the complex haemodynamic interplay between LVOT obstruction and concomitant AS and disentangling these lesions by meticulous invasive assessment. ASA can be performed safely and successfully in patients with coexisting LVOT obstruction and severe AS.

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Haemodynamic Interplay Between Concomitant LV Outflow Tract Obstruction and Aortic Stenosis 1.

4. 5.

6. 7.

De Bruyne B, Pijls NH, Heyndrickx GR, et al. Pressurederived fractional flow reserve to assess serial epicardial stenoses: theoretical basis and animal validation. Circulation 2000;101:1840–7. https://doi.org/10.1161/01.CIR.101.15.1840; PMID: 10769286. El Masry H, Breall JA. Alcohol septal ablation for hypertrophic obstructive cardiomyopathy. Curr Cardiol Rev 2008;4:193–7. https://doi.org/10.2174/157340308785160561; PMID: 19936195. Scantlebury DC, Geske JB, Nishimura RA. Limitations of Doppler echocardiography in the evaluation of serial stenoses. Circ Cardiovasc Imaging 2013;6:850–2. https://doi. org/10.1161/CIRCIMAGING.113.000575; PMID: 24046382. Halpern EJ. Cardiac morphology and function. In: Halpern AJ, Owen AN, eds. Clinical Cardiac CT: Anatomy and Function. New York, NY: Thieme; 2008, 166–75. Nishimura RA, Carabello BA. Hemodynamics in the cardiac catheterization laboratory of the 21st century. Circulation 2012;125:2138–50. https://doi.org/10.1161/ CIRCULATIONAHA.111.060319; PMID: 22547754. Trevino AR, Buergler J. The Brockenbrough-BraunwaldMorrow sign. Methodist Debakey Cardiovasc J 2014;10:34–7. https://doi.org/10.14797/mdcj-10-1-34; PMID: 24932361. Bishu K, Coylewright M, Nishimura R. The role of

10.

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hemodynamic catheterization in the evaluation of hypertrophic obstructive cardiomyopathy: a case series. Catheter Cardiovasc Interv 2015;86:903–12. https://doi. org/10.1002/ccd.25856; PMID: 25620326. Kim LK, Swaminathan RV, Looser P, et al. Hospital volume outcomes after septal myectomy and alcohol septal ablation for treatment of obstructive hypertrophic cardiomyopathy: US Nationwide inpatient database, 2003–2011. JAMA Cardiol 2016;1:324–32. https://doi.org/10.1001/jamacardio.2016.0252; PMID: 27438114. El-Jack SS, Nasif M, Blake JW, et al. Predictors of complete heart block after alcohol septal ablation for hypertrophic cardiomyopathy and the timing of pacemaker implantation. J Interv Cardiol 2007;20:73–76. https://doi. org/10.1111/j.1540-8183.2007.00220.x; PMID: 17300408. Faber L, Welge D, Fassbender D, et al. Percutaneous septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: managing the risk of procedure-related AV conduction disturbances. Int J Cardiol 2007;119:163–7. https:// doi.org/10.1016/j.ijcard.2006.07.179; PMID: 17067708. Alam M, Dokainish H, Lakkis N. Alcohol septal ablation for hypertrophic obstructive cardiomyopathy: a systematic review of published studies. J Interv Cardiol 2006;19:319–27. https://doi.org/10.1111/j.1540-8183.2006.00153.x;

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PMID: 16881978. 12. Chang SM, Nagueh SF, Spencer WH 3rd, Lakkis NM. Complete heart block: determinants and clinical impact in patients with hypertrophic obstructive cardiomyopathy undergoing nonsurgical septal reduction therapy. J Am Coll Cardiol 2003;42:296–300. https://doi.org/10.1016/S07351097(03)00623-5; PMID: 12875767. 13. Qin JX, Shiota T, Lever HM, et al. Outcome of patients with hypertrophic obstructive cardiomyopathy after percutaneous transluminal septal myocardial ablation and septal myectomy surgery. J Am Coll Cardiol 2001;38:1994–2000. https://doi.org/10.1016/S0735-1097(01)01656-4; PMID: 11738306. 14. Liebregts M, Vriesendorp PA, Mahmoodi BK, et al. A systematic review and meta-analysis of long-term outcomes after septal reduction therapy in patients with hypertrophic cardiomyopathy. JACC Heart Fail 2015;3:896–905. https:// doi.org/10.1016/j.jchf.2015.06.011; PMID: 26454847. 15. Veselka J, Duchonová R, Procházková S, et al. The biphasic course of changes of left ventricular outflow gradient after alcohol septal ablation for hypertrophic obstructive cardiomyopathy. Kardiol Pol 2004;60:133–6. PMID: 15116158.

Posters from JIM 2021 Predictors of In-Hospital Outcomes among Octogenarians with Acute ST-elevation Myocardial Infarction at the Philippine Heart Center Emily Mae L Yap and Alexander A Tuazon Invasive Cardiology Division, Philippine Heart Center, Quezon City, the Philippines

Keywords

STEMI, Filipino, octogenarians, reperfusion Citation: Interventional Cardiology Review 2021;16:e12. DOI: https://doi.org/10.15420/icr.2021.16.PO1 Correspondence: Emily Mae L Yap, Invasive Cardiology Division, Department of Adult Cardiology, Philippine Heart Center, East Avenue, Quezon City, the Philippines. E: emilymaeyap@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Background: Studies among very elderly Filipinos with acute ST-elevation MI (STEMI) are limited. Aim: To determine the clinical profile, treatment strategies and predictors of in-hospital outcome on Filipino octogenarians.

Table 1: Clinical Characteristics of Octogenarians with Acute STEMI at the Philippine Heart Center, 2014–2018 (n=71) Frequency (%) Age, mean ± SD

84.11 ± 2.40

Sex Male Female

35 (49.3) 36 (50.7)

Location of MI Anterior Inferior Lateral

38 (53.52) 27 (38.03) 6 (8.45)

Results: There were 71 octogenarians in our cohort with a mean age of 84.11 ± 2.40 years. The most common infarct location was the anterior wall (53.52%). Primary PCI (PPCI) was the reperfusion therapy of choice in 47 octogenarians with angiographic success achieved in 43 cases. There were five patients who expired in the PPCI group. Among the 21 patients who were managed conservatively, 12 expired. Fibrinolysis was performed in only three cases. Cardiogenic shock was the most common major adverse cardiovascular event (MACE) (18, 25.35%). The mean ejection fraction (EF) of our cohort was 47.45 ± 10.82%. A higher EF was associated with a lower risk of developing MACE and/or in-hospital mortality (OR 0.91, p=0.008). Killip Class 4 (OR 8.32, p=0.034), two/three-vessel involvement (OR 2.77, p=0.008) and contrast-induced acute kidney injury (CI-AKI) (OR 6.39, p=0.015) were associated with a higher risk of developing MACE and/or in-hospital mortality.

Killip Killip 1 Killip 2 Killip 3 Killip 4

30 (42.25) 15 (21.13) 10 (14.08) 16 (22.54)

TIMI TIMI 1 (%) TIMI 2 (%) TIMI 3 (%) TIMI 4 or higher

6 (8.45) 20 (28.17) 11 (15.49) 34 (47.89)

SBP (mm Hg) on presentation, mean ± SD

114.54 ± 23.49

DBP (mm Hg) on presentation, mean ± SD

67.17 ± 12.09

HR (BPM), mean ± SD HR >l00 Normal HR HR <50

75.07 ± 20.39 9 (12.68) 54 (76.06) 8 (11.27)

Conclusion: Octogenarians who underwent PPCI had better outcomes compared to those who were managed medically. A higher ejection fraction was associated with a lower risk of MACE and/or in-hospital mortality. Killip Class 4, multivessel involvement and CI-AKI were independent predictors of MACE and/or in-hospital mortality.

Comorbidities Hypertension Diabetes Prior stroke Chronic obstructive pulmonary disease Dyslipidaemia Chronic kidney disease Prior MI Prior coronary artery bypass grafting

25 (35.21) 26 (36.62) 10 (14.08) 7 (9.86) 7 (9.86) 6 (8.45) 5 (7.04) 2 (2.82)

Smoker

33 (46.48)

Ejection fraction by Simpson’s method (%) Normal LV function (≥50%) Mild LV dysfunction (40–49%) Moderate LV dysfunction (30–39%) Severe LV dysfunction (<30%)

47.45 ± 10.82 22 (30.99) 21 (29.58) 26 (36.62) 2 (2.82)

Duration of hospitalisation (days), mean ± SD

5.32 ± 2.51

Methods: A retrospective cross-sectional study was conducted at the Philippine Heart Center on all patients who were 80 to 89 years old with acute ST-elevation myocardial infarction (STEMI) from 1 January 2014 to 31 December 2018. Predictors of major adverse cardiovascular events (MACE) and/or in-hospital mortality were determined using binary logistic regression analysis.

Posters from JIM 2021 Radiation Dose in Coronary Angiography and Percutaneous Coronary Intervention: Establishment of Diagnostic Reference Levels at the Philippine Heart Center Emily Mae L Yap, Livy P Magno, Christopher A Macaraeg, Gilbert E Pedroso, Aeron G Ramos, Mardy Zaldess S Cruz, Alexander A Tuazon, Ronaldo H Estacio, Ramoncito B Tria Invasive Cardiology Division, Philippine Heart Center, Quezon City, the Philippines

Keywords

Radiation level, diagnostic reference level, dose area product, fluoroscopy time Citation: Interventional Cardiology Review 2021;16:e13. DOI: https://doi.org/10.15420/icr.2021.16.PO2 Correspondence: Emily Mae L Yap, Invasive Cardiology Division, Department of Adult Cardiology, Philippine Heart Center, East Avenue, Quezon City, the Philippines. E: emilymaeyap@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Background: With the continuing rise in the number of patients undergoing coronary angiography (CA) and percutaneous coronary interventions (PCI), the significance of radiation safety should always be underscored. Aim: To establish the first local diagnostic reference levels (DRLs) for CA, elective PCI and ad hoc PCI at the Philippine Heart Center. Methods: A retrospective review of the medical records of all consecutive patients who underwent CA and PCI from May 1 to December 31, 2019 was done. The DRLs were set from the third quartile (75th percentile) of the median total dose area product (DAP) for each procedure. Results: There were 2,790 patients in the CA group with a median fluoroscopy time (FT) of 2.7 minutes (interquartile range [IQR] 1.48–5.6),

total DAP of 16.6 Gy.cm2 (IQR 11.2–24.9) and DRL of 24.9 Gy.cm2. There were 697 patients in the elective PCI group with a median FT of 9.1 minutes (IQR 4.8–15.1), total DAP of 62.3 Gy.cm2 (IQR 32.4–122) and DRL of 122.04 Gy.cm2. There were 587 patients who underwent single-vessel ad hoc PCI with a median FT of 9.6 minutes (IQR 5.7–13.7), total DAP of 41.6 Gy.cm2 (IQR 30.8–68.2) and DRL of 68.2 Gy.cm2. Higher radiation doses based on the total DAP were seen when the femoral access was used compared to the radial access for CA (18.5 versus 16.2, p<0.001), elective PCI (88.3 versus 52.7, p<0.001) and ad hoc PCI (45.4 to 38.8, p<0.001). Conclusion: Higher radiation doses were consistently observed when the transfemoral approach was used which suggests that use of the radial access can potentially lower radiation exposure. The local DRLs established may be used as a point of reference for other cardiac catheterisation laboratories in our country.

Table 1: Radiation Doses Recorded During Coronary Angiography, Elective Percutaneous Coronary Intervention and Ad Hoc Percutaneous Coronary Intervention CA

PCI*

One Vessel PCI

Two Vessel PCI

Three Vessel PCI Ad Hoc PCI†

Median (IQR) Fluoroscopy time (mins)

2.7 (1.48–5.6)

9.1 (4.8–15.1)

8.1 (4.4–14.3)

11.4 (8–14)

8.7 (4.4–17.3)

9.6 (5.7–13.7)

714.6 (345.3–1,281.7)

434.3 (257.6–723.2)

671.2 (413–1,075.5)

1,174.2 (781–1,881)

507.6 (339.3–856.9)

5.4 (2.9–11.3)

40 (20.2–85.8)

24.4 (12.2–42.1)

36.4 (22.3–67.6)

88.0 (45.3–130)

23.6 (16–44.7)

10 (7.28–13.9)

17.5 (10.9–29.6)

14.1 (7.4–23.4)

15.8 (8.62–30.9)

22.5 (15.1–40.2)

17.8 (12.9–24.2)

16.6 (11.2–24.9)

62.3 (32.4–122)

41.5 (23.2–70.1)

57.7 (33.6–98.6)

116 (71.1–174.5)

41.6 (30.8–68.2)

24.9

122.04

70.1

98.6

174.51

68.2

Cumulative air kerma (mGy) 188.7 (122.1–291) DAP fluoroscopy DAP exposure

(Gy.cm2)

Total DAP (Gy.cm2) DRL

(Gy.cm2)

* Regardless of the number of vessels involved. †Ad hoc PCI for single vessels only. CA = coronary angiography; DAP = dose area product; DRL = diagnostic reference level; IQR = interquartile range; PCI = percutaneous coronary intervention.

Posters from JIM 2021 A Staged Hybrid Approach to an Aberrant Right Subclavian Artery with Symptomatic Kommerell’s Diverticulum Krystal Dinh, Lucy Manuel, Kalpa Perera and Thomas Daly Westmead Hospital, Sydney, Australia

Citation: Interventional Cardiology Review 2021;16:e14. DOI: https://doi.org/10.15420/icr.2021.16.PO3 Correspondence: Krystal Dinh, Westmead Hospital, Westmead Sydney, NSW 2145, Australia. E: dinhkrystal9@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Case Report

A 78-year-old man presented with tearing chest pain with associated dyspnoea and dysphagia. He was an ex-smoker with no personal or family history of connective tissue disorders. CT angiography illustrated an aberrant right subclavian artery, coursing posterior to the trachea and oesophagus, with an associated 4.4 cm Kommerell’s diverticulum (Figure 1). Imaging also illustrated tracheal stenosis and oesophageal compression. A coronary angiogram demonstrated severe double vessel coronary artery disease. A staged procedure with aortic arch debranching and CABG (Figure 2), followed by a thoracic stent graft and Amplatzer plug to address the Kommerrel’s diverticulum was undertaken.

was no immediate noticeable difference in swallowing; however, his breathing had improved. Given CT angiography illustrated a non-dominant right vertebral artery, with known collateralisation to the arm, a decision was made not to perform a carotid subclavian bypass. Unfortunately, at routine 4-week follow-up the patient reported pre-syncopal episodes with associated right-hand paraesthesia, likely explained by vertebral-basilar insufficiency. A right carotid-subclavian artery bypass was performed to correct this.

His post-operative recovery was complicated by AF, hospital acquired pneumonia and delirium requiring reintubation for severe agitation. There

There were no immediate post-operative complications and the patient was discharged home. At 6-week follow-up, he had improved right hand symptoms with no further pre-syncopal episodes and had improved swallow.

Figure 1: CT Reconstruction Illustrating Kommerell’s Diverticulum and an Aberrant Right Subclavian Artery

Figure 2: CT Reconstruction Illustrating a Debranched Left Common Carotid Artery and Subclavian Artery

There is a double coronary artery bypass graft (left internal mammary artery to left anterior descending, and saphenous vein T graft to obtuse marginal artery).

JIM 2021 Posters Figure 3: Angiography Illustrating Kommerell’s Diverticulum Before and After Deployment of Amplatzer Plug to Right Subclavian and Thoracic Aortic Stent Graft

Discussion

Given the scarce evidence base, management should be tailored on a case by case basis to the individual patient. Surgical treatment remains controversial and should be considered if patients are symptomatic with some suggestion of a Kommerell’s diverticulum of >3cm being an 1.

Vinnakota A, Idrees JJ, Rosinski BF, et al. Outcomes of repair of Kommerell diverticulum. Ann Thorac Surg 2091;108:1745–50. https://doi.org/10.1016/j. athoracsur.2019.04.122; PMID: 31254511. 2. Tanaka A, Milner R, Ota T. Kommerell’s diverticulum in the current era: a comprehensive review. Gen Thorac Cardiovasc Surg 2015;63:245–59. https://doi.org/10.1007/s11748-0150521-3; PMID: 25636900. 3. Idrees J, Keshavamurthy S, Subramanian S, et al. Hybrid

indication for operating in a low-risk patient.1 Open, endovascular and hybrid procedures have all been successfully performed with acceptable rates of morbidity and mortality.2 This suggests that the choice of treatment should be tailored to the patient-specific anatomy, associated morbidity, and expertise of the treating surgical team.5

repair of Kommerell diverticulum. J Thorac Cardiovasc Surg 2014;147:973–6. https://doi.org/10.1016/j.jtcvs.2013.02.063; PMID: 23535153. 4. Kieffer E, Bahnini A, Koskas F. Aberrant subclavian artery: surgical treatment in thirty-three adult patients. J Vasc Surg 1994;1:100–11. https://doi.org/10.1016/s0741-5214(94)70125-3; PMID: 8301723. 5. van Bogerijen GH, Patel HJ, Eliason JL, et al. Evolution in the management of aberrant subclavian arteries and related

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Kommerell diverticulum. Ann Thorac Surg 2015;100:47–53. https://doi.org/10.1016/j.athoracsur.2015.02.027; PMID: 24997809. 6. Youssef A, Ghazy T, Kersting S, Leip JL, Hoffmann RT, Kappert U, et al. Management of the left subclavian artery during TEVAR – complications and mid-term follow-up. Vasa 2018;47:387–92.https://doi.org/10.1024/0301-1526/a000713; PMID: 29788799.

Posters from JIM 2021 Endovascular Treatment of a Large Iatrogenic Popliteal Arteriovenous Fistula Krystal Dinh, Andrew Ying, Rafid Al-Asady and Mauro Vicaretti Westmead Hospital, Sydney, Australia

Citation: Interventional Cardiology Review 2021;16:e15. DOI: https://doi.org/10.15420/icr.2021.16.PO4 Correspondence: Krystal Dinh, Westmead Hospital, Westmead, Sydney, NSW 2145, Australia. E: dinhkrystal9@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

An arteriovenous fistula (AVF) is an abnormal communication between an artery and a vein, resulting in pressurisation of the venous circulation and increases in size and flow of both vessel systems. AVFs have an important therapeutic use in haemodialysis access, but can also be pathologic. Here, we present the case of an uncommonly large and chronic AVF in the popliteal fossa, probably secondary to previous knee surgery.

Figure 1: The Patient’s Lower Limbs

A 40-year-old man presented with years of progressive leg swelling and venous varicosities. Lower limb computed tomography angiography and subsequent digital subtraction angiography demonstrated a large popliteal arteriovenous fistula (AVF). This was treated successfully by endovascular technique with a Viabahn stent (WL Gore) in the popliteal artery to exclude the AVF. AVFs of this size and chronicity are rare, and this case demonstrates a successful endovascular method of treatment. AVFs of the lower extremity are uncommon, particularly of the size and chronicity reported here. Causes are primarily traumatic or iatrogenic, but spontaneous cases due to aneurysmal dilation from Marfan disease, human immunodeficiency virus arteritis, and unknown causes have also been reported. Complications without repair may include symptoms of venous congestion with subsequent venous ulceration, venous thromboembolism, arterial steal, and high-output cardiac failure. Surgical options include open surgical repair, endovascular repair, and a combination of open surgery and endovascular techniques. It was the authors’ opinion to undertake endovascular repair because of the large and multiple arterialised varicosities in the popliteal fossa. Endovascular options include covered stent, coil embolisation, and insertion of vascular plugs. It was the authors’ preferred option to proceed to covered stent alone because of the anatomic configuration in this case.

The size discrepancy and venous varicosities on the left leg can be seen.

JIM 2021 Posters Figure 2: 3D Reconstruction of Lower Limb CT Angiography Showing Left Leg Arterial and Venous Dilation with Extensive Venous Varicosities in the Left Calf

Figure 4: Digital Subtraction Angiography of the Below-knee Runoff Vessels with Temporary Occlusion of Flow Through the Arteriovenous Fistula Using a Fogarty Balloon

Figure 3: Digital Subtraction Angiography of Popliteal Artery Showing Large Arteriovenous Fistula and Flow Into Popliteal Vein Figure 5: Digital Subtraction Angiography After Stenting Showing Exclusion of the Arteriovenous Fistula

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Posters from JIM 2021 Vascular Tracheobronchial Compression Syndrome Secondary to Contained Ruptured Thoracic Aortic Aneurysm Krystal Dinh, Lucy Manual and Mauro Vicaretti Westmead Hospital, Sydney, Australia

Citation: Interventional Cardiology Review 2021;16:e16. DOI: https://doi.org/10.15420/icr.2021.16.PO5 Correspondence: Krystal Dinh, Westmead Hospital, Westmead Sydney, NSW 2145, Australia. E: dinhkrystal9@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

A 40-year-old man presented to ED with sudden onset dyspnoea and severe chest pain radiating to his back. He also reported a year-long history of intermittent haemoptysis. On presentation, the patient’s observations were stable. The patient was born and raised in Tibet and reported having previously been treated for confirmed tuberculosis.

Figure 1: Chest Xray Illustrating Complete Collapse of the Left Lung Lobe

On CTA, the patient was found to have a large saccular aneurysm measuring 5.0 × 5.0 × 5.0 cm, arising from a focal location of the proximal descending thoracic aorta distal to the origin of the left subclavian artery with evidence of contained rupture. The mass was found to be causing significant external compression of the left main bronchus leading to significant effacement of the left main primary bronchi leading to extensive collapse in both left upper and lower lobes and overall reduction in volume of the left hemithorax. An open repair was done to exclude the thoracic aneurysm and to also relieve compression from the bronchus. The saccular aneurysm was opened, an old clot was evacuated and the area dissected to its neck at the inferior arch. Nil communication with the bronchus was evident. The remaining aorta appeared relatively normal. The edges of the aneurysm neck were fashioned towards healthy aorta and the resulting defect closed, primarily with a single layer of bilaterally buttressed. Left lung recruitment achieved eventual satisfactory re-expansion.

pneumonia, which was subsequently treated with a course of IV tazocin.

Post-operatively, the patient experienced intermittent episodes of desaturation secondary to mucous plugging. The patient required regular chest physiotherapy, hi flow nasal prongs for humidification and intermittent bilevel positive airway pressure. He also developed hospital-acquired

A repeat CTA illustrated good flow through the thoracic aneurysm, re expansion of the left lung, and decompression of the left main bronchus. Histopathology of washing and fine needle aspirates were all negative for tuberculosis and bacteria.

JIM 2021 Posters Figure 2: Contained Thoracic Aneurysm Rupture

Figure 3: Ruptured Thoracic Aneurysm Compressing the Left Main Bronchus

Sebening C, Jakob H, Tochtermann U, et al. Vascular tracheobronchial compression syndromes – experience in surgical treatment and literature review. Thorac Cardiovasc Surg 2000;48:164–74. https://doi.org/10.1055/s-2000-9633. PMID: 10903065. 2. Kanabuchi K, Noguchi N, Kondo T. Vascular tracheobronchial compression syndrome in adults: a review. Tokai J Exp Clin Med 2011;36:106–11. PMID: 22167491. 3. Kumar A, Dutta V, Negi S, Puri GD. Vascular airway compression management in a case of aortic arch and descending thoracic aortic aneurysm. Ann Card Anaesth 2016;19:568–71. https://doi. org/10.4103/0971-9784.185568. PMID: 27397474.

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Posters from JIM 2021 Three Years’ Libyan Experience in Congenital Heart Disease Interventions M Madany, S Rahouma, A Khazmi, R AL Fitouri and S Rahouma National Heart Center, Benghazi, Libya

Keywords

National Heart Center Benghazi, congenital heart disease, atrial septal defect, patent foramen ovale, patent ductus arteriosus, transposition of the great arteries, pulmonary stenosis Citation: Interventional Cardiology Review 2021;16:e17. DOI: https://doi.org/10.15420/icr.2021.16.PO6 Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Interventional cardiology procedures are constantly increasing in management of structure heart disease in developing countries, such as Libya. The aim of the study was to review the Libyan experience in congenital heart intervention in the eastern region of Libya during the period 2017–2020. National Heart Center Benghazi is a referral centre in the eastern region of Libya. Formerly the Benghazi Cardiac Center, it offers services to children with congenital heart disease from different cities across Libya. The service includes diagnosis and transcatheter intervention in newborns, infants, paediatrics and adults with congenital heart disease. Diagnostic and interventional catheterisation carried out solely by the Libyan congenital cardiology team alone started in 2007/2008. During the 3 years (2017–2020) of the study, patients were referred to our centre from different cardiac clinic and general hospitals in Libya. We

restarted work after a critical period in our city after the war. We started work in repairing and rebuilding the centre, resulting in limited number of cases compared to other centres. We performed around 85 structural heart disease interventional and diagnostic cases. Of these cases, 22 were atrial septal defects/patent foramen ovale transcatheter closure, 19 were patent ductus arteriosus, transcatheter closure, 18 were pulmonary balloon valvuloplasty, five Rashkind atrial septostomy, 19 were diagnostic catheterisations, one was balloon angiography to COA stent and two were coronary angiography for post transposition of great arteries repair and post Kawasaki disease with coronary dilation. Conclusion: In Libya, there has been a steady growth in the intervention and diagnostic procedures in structural heart disease.

Posters from JIM 2021 Single Operator Observational Study of Incidence of Pocket Site Infection and Safety of Absorbable Sutures for Pocket Closure of Cardiac Implantable Electronic Devices Inderjeet Singh Monga Command Hospital (Western Command) Chandimandir, Panchkula, India

Citation: Interventional Cardiology Review 2021;16:e18. DOI: https://doi.org/10.15420/icr.2021.16.PO7 Correspondence: Lt Col Inderjeet Singh Monga, Classified Specialist (Medicine and Cardiology), Command Hospital (Western Command) Chandimandir, Panchkula, India. E: docinder_86123@rediffmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Aim: To present one operator’s 4-year experience on the safety of pocket closure using single absorbable subcuticular suture Vicryl 2-0 at various armed forces and civilian centres.

Figure 1: Other Advantages – Aesthetic Look and Reduced Hospital Stay

Methods: This is a single operator observational study. Between January 2017 and December 2020, a total of 365 patients underwent device implantation for various indications at different hospital of armed forces and civil by the author. Results: All 365 cases underwent pocket closure using three layers of single continuous absorbable subcuticular suture with Vicryl 2-0 in 364 (99.7%) and Monocryl 2-0 in 1 (0.27%) patient. CIED distribution was: AICD single chamber-34 (24.5%), PPI single chamber-131 (35.9%), AICD dual chamber-13 (3.6%), PPI dual chamber-130 (35.6%), CRT P/D-3 (0.8%), AICD PGR-9 (2.5%), CRT PGR-4 (1.1%) and PPI PGR 41 (11.2%). There were 52 (14.2%) patients on dual antiplatelet therapy (DAPT) and nine (2.46%) patients on oral anticoagulants. Ages ranged from 4 years to 92 years (average age 66 ± 1.6 years). 128 patients (35%) were female and 227 (65%) were male. 124 patients (33.9%) were diabetic. All patients received minimum 5 days in-hospital IV antibiotics and 96.7% patients were discharged on day 5 post-op. Average in-hospital stay was 5.7 days. Twelve (3.28%) patients developed pocket site infection with no mortality. In four patients, infection was superficial not communicating with pocket. It healed with prolonged antibiotics for 1 extra week. Eight (66.7%) of these patients underwent device re-implantation subpectoral on same side with help of reconstructive surgeon and five (62.5%) devices were salvaged. Thus three (0.82%) patients required device explantation and procedure completed from contralateral side same day. All three patients were females in physically active age group. Two (66.67%) of these were diabetic, while one (33.33%) was on DAPT. In comparison only one patient who underwent pocket closure using Moncryl 2-0 was explanted. Conclusion: Pocket closure using three layers of single continuous absorbable subcuticular suture Vicryl 2-0 has been found to be very safe

The immediate look post suturing (left) and the look during follow-up (right).

Figure 2: Comparison with Other Methods

The look after suturing with staples and skin sutures (left) and the look during follow-up and keloid formation (right).

and effective modality for pocket closure and also helps in reducing pocket infection. In our experience after using this suture device, explantation rate was only 0.55% and device healing success rate was 99.45%. It is convenient for the patients too, as total duration of in-hospital stay as well as post discharge visits are reduced significantly. It also gives an aesthetic look which is especially appealing in young females. Monocryl 2-0 has not been found to be a good alternative as device explantation rate using this suture was 100%. We also found that device salvage therapy using subpectoral pocket and negative pressure wound therapy by reconstructive surgeons has shown a success rate of 62.5%.

Posters from JIM 2021 Single Centre Observational Study on Clinical Profile and Optical Coherence Tomography-guided Management Strategy for Patients with Young Acute Coronary Syndrome Inderjeet Singh Monga,1 Anil Kumar,2 R Girish1 and AK Sood1 1. Command Hospital (Western Command), Panchkula, India; 2. 7 Air Force Hospital, Kanpur, India

Citation: Interventional Cardiology Review 2021;16:e19. DOI: https://doi.org/10.15420/icr.2021.16.PO8 Correspondence: Lt Col Inderjeet Singh Monga, Command Hospital (Western Command) Chandimandir, Panchkula, India. E: docinder_86123@rediffmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Aim: To present our experience of study of clinical profile and optical coherence tomography (OCT) guided management of young patients (<45 years) presenting with acute coronary syndrome (ACS) during the study period. Methods: This is a single centre observational study. A total of 119 cases with age <45 years of acute coronary syndrome, who underwent cardiac evaluation with coronary angiography and proceed at our hospital during study period October 2019 to September 2020 were included. Findings and results: All patients were men. Age ranged from 23 years to 45 years. All the patients survived (mortality nil). The most common presentation was unstable angina in 57 (47.9%), STelevation MI in 46 (38.6%), with further subdivision into 28 (60.8%) anterior wall MI, 12 (26.1%) as inferior wall MI and six (13.0%) patients as true posterior wall MI. The remaining 14 (11.7%) patients had non-ST-elevation MI. The most common coronary angiogram finding was patent coronaries with slow flow in 64 (53.8%) patients, while obstructive coronary artery disease (CAD) was seen in 55 (46.2%) patients with distribution of single vessel disease (SVD) in 37 (67.3%), double vessel disease (DVD) in 12 (21.8%) and triple vessel disease (TVD) in the remaining six (10.9%) patients.

Left anterior descending artery (LAD) was the most common vessel involved in 33 (60%), followed by right coronary artery (RCA) in 14 (25.5%) and left circumflex artery (LCx) in eight (14.5%) patients Of the 55 patients diagnosed with obstructive CAD, 31 patients (56.4%) had large intracoronary thrombus burden in the culprit vessel. Of these, 14 patients (45.1%) overall, and 85.7% in particular belonging to high altitude areas (HAA), underwent deferred stenting intracoronary lysis with either tPA 10 mg or TNK 5–8 mg (1/5 dose depending on body weight). This was followed by GP IIb IIIa infusion for 24 hours and then a 7-day course of low molecular weight heparin (LMWH) at a dosage of 1g/kg twice daily. Thereafter all these patients underwent check coronary angiogram and OCT study. After following this novel approach, only two (14.3%) required stenting as OCT revealed plaque rupture. Thus in 85.7% of this cohort stenting could be avoided. Conclusion: Young ACS is a substrate that needs to be studied for the presence of traditional as well as specific risk factors. In our study population cohort, 59.3% patients were posted in HAA and approximately 40% of these were smokers too. With the use of deferred stenting and OCT guidance, we managed to avoid stenting in approximately 85.7% of patients in this substrate with high thrombus burden on initial angiogram.

Figure 1: Coronary Risk Factors in All Subjects

JIM 2021 Posters Figure 2: Example 1

Figure 3: Example 2

Figure 4: Example 3

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Posters from JIM 2021 Clinical Experience of Percutaneous Coronary Intervention for Severely Calcified Coronary Artery Lesions with Orbital Atherectomy System Jumpei Koike, Yoshihiro Iwasaki, Toshinori Ko, Atsushi Funatsu, Tomoko Kobayashi and Shigeru Nakamura Kyoto Katsura Hospital, Japan

Citation: Interventional Cardiology Review 2021;16:e20. DOI: https://doi.org/10.15420/icr.2021.16.PO9 Correspondence: Jumpei Koike, Kyoto Katsura Hospital, Japan. E: j.koipei232364@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Background: Severely calcified lesions present many challenges to percutaneous coronary intervention (PCI). Recently, a newly developed atherectomy device, Diamondback coronary orbital atherectomy system (OAS) has been approved. Aim: We enrolled 292 consecutive cases (374 lesions) who underwent PCI with OAS in Kyoto Katsura Hospital from February 2018 to November 2020. We assessed the clinical outcomes after OAS of severely calcified lesions; procedure success, angiographic complications, in-hospital major adverse cardiac events (MACE; cardiac death, MI [MI: CK-MB > 10 × ULN] and target vessel/lesion revascularisation [TVR/TLR]) and mid-term results at 8 months after PCI. Results: Mean age was 76 years old and 75% of the patients were men. De novo lesions were 83% and in stent restenosis (ISR) was 7%. Optical frequency domain imaging (OFDI) was used as the imaging device in 54%

of cases. We performed OAS at low revolution speed in all cases and made an addition at high revolution speed in 67% of lesions, while 9% of lesions needed rotational atherectomy. Eight-four per cent of lesions were treated with drug coated-balloons (DCB), and stents were implanted in 14% of lesions. Procedural success rate was 97%. In complications, coronary perforation occurred in 1% of lesions and persistent slow flow in 2%. In in-hospital MACE, there were 23 nonQ MI (8%), one cardiac death (0.5%), and no TLR. In post-discharge MACE, there were no cardiac deaths and no MI, but 8% TLR. Follow-up angiography was performed in 180 of 273 lesions (66%) that were eligible for follow-up at 8 months. Restenosis was observed in 10% of lesions. Conclusion: OAS has been shown to have high procedure success rate and low restenosis rate. OAS is going to be another option for reducing calcified plaque.

Posters from JIM 2021 Patient Radiation Exposure During Primary Percutaneous Coronary Intervention in Acute ST-elevation Myocardial Infarction at the Philippine Heart Center Emily Mae L Yap, Christopher Macaraeg, Richard Ayuson, Alexander Tuazon, Ronaldo Estacio and Ramoncito Tria Invasive Cardiology Division, Philippine Heart Center, Quezon City, the Philippines

Keywords

STEMI, radiation dose, diagnostic reference level Citation: Interventional Cardiology Review 2021;16:e21. DOI: https://doi.org/10.15420/icr.2021.16.PO10 Correspondence: Emily Mae L Yap, Invasive Cardiology Division, Department of Adult Cardiology, Philippine Heart Center, East Avenue, Quezon City, the Philippines. E: emilymaeyap@hotmail.com. Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Background: Emergency procedures, such as primary percutaneous coronary intervention (PCI) in the setting of acute ST-elevation MI (STEMI), may entail longer procedural times which translate to higher radiation exposure. In an effort to further improve radiation safety practices, the determination of the diagnostic reference level (DRL) for these procedures may allow the identification of practices which may predispose patients and operators to the undesirable effects of radiation. Aim: This study aims to determine the radiation doses of the patients who underwent primary PCI in the setting of STEMI and to set the DRL for this procedure in our cardiac catheterisation laboratory. Methods: This was a retrospective cohort study conducted at the Philippine Heart Center (PHC) on all patients with STEMI who underwent primary PCI from 1 May 2019 to 29 February 2020. The DRL was established based on the third quartile values of the median dose area products.

Results: There were 663 consecutive STEMI patients who underwent primary PCI, with a mean age of 55.75 ± 11.45 years. There were significantly more patients who underwent primary PCI using the transradial approach (395, 59.58%) compared to the transfemoral approach (268, 40.42%; p<0.001). For both approaches, the median fluoroscopy time was 11.05 minutes (7.23–16.38). The median cumulative air kerma was 496.46 mGy (330.95–842.8). The median total DAP was 4.22 mGy.m2 (interquartile ratio 2.78–6.55) and the DRL was 6.55 mGy.m2. A significantly higher DRL was seen when the femoral access was used (6.74 versus 6.50, p<0.001). Conclusion: Higher radiation exposure can occur during emergency procedures compared to elective cases. Compared to the established DRL for elective ad hoc PCI in other countries, we report a higher local DRL, highlighting the need to reduce radiation exposure to as low as reasonably achievable for the operators.

JIM 2021 Posters Table 1: Clinical and Procedural Characteristics of Patients Total (n=663)

Radial (n=395)

Femoral (n=268)

p-value

Frequency (%), mean ± SD Age

55.75 + 11.45

55.04 + 10.48

56.78 + 12.69

0.055

Sex Male Female

530 (79.94) 133 (20.06)

314 (79.49) 81 (20.51)

216 (80.60) 52 (19.40)

0.728

Hypertension Diabetes Prior stroke

345 (52.04) 102 (15.38) 21 (3.17)

202 (51.14) 60 (15.19) 10 (2.53)

143 (53.36) 42 (15.67) 11 (4.10)

0.575 0.866 0.256

Onset of chest pain (hours)

6.85 ± 4.36

7.02 ± 3.75

6.60 ± 5.12

0.2281

Inter-hospital transfer Primary ER

447 (67.42) 216 (32.58)

249 (63.04) 146 (36.96)

198 (73.88) 70 (26.12)

0.003

Door-to-wiring time (mins) Door-to-balloon (mins)

25 (20–34) 29 (23–38)

25 (20–32) 28 (23–36)

27 (21–36) 30 (24–40)

0.049 0.007

Infarct-related artery LAD LCX RCA

455 (68.63) 40 (6.03) 168 (25.34)

290 (73.42) 25 (6.33) 80 (20.25)

165 (61.57) 15 (5.60) 88 (32.84)

0.001

Left main involvement

27 (4.07)

8 (2.03)

19 (7.09)

0.001

PCI of the infarct-related artery only

411 (61.99)

271 (68.761)

140 (52.24)

<0.001

POBA of the infarct-related artery

30 (4.52)

17 (4.30)

13 (4.85)

0.740

Complete revascularization

112 (45.34)

53 (44.17)

59 (46.46)

Staged PCI

135 (54.66)

67 (55.83)

68 (53.54)

DES 1 stent 2 stents 3 or more stents

436 (65.76) 111 (16.74) 61 (9.2)

284 (71.90) 63 (15.95) 32 (8.1)

152 (56.72) 48 (17.91) 29 (10.82)

0.065

Volume of contrast (ml)

90 (80–110)

80 (75–100)

100 (80–120)

<0.001

Alive Expired

618 (93.21%) 45 (6.79%)

362 (91.65%) 33 (8.35%)

256 (95.52%) 12 (4.48%)

0.051

0.718

Table 2: Radiation Doses During Primary Percutaneous Coronary Intervention Total (n=663)

Radial (n=395)

Femoral (n=268)

p-value

Median (IQR) Fluoroscopy time (mins)

11.05 (7.23–16.38)

10.43 (7.02–16.03)

11.215 (7.75–16.9)

0.158

DAP fluoroscopy (Gy.cm2)

2.4 (1.53–4.21)

2.39 (1.42–4.03)

2.49 (1.64–4.27)

0.194

1.77 (1.20–2.5)

1.77 (1.21–2.46)

1.75 (1.19–2.57)

0.929

DAP exposure Total DAP

(Gy.cm2)

4.22 (2.78–6.55)

4.195 (2.7–6.5)

4.3 (2.89–6.74)

0.162

Estimated effective dose (mSV)

7.81 (5.14 to 12.12)

7.76 (5 to 12.03)

7.96 (5.35 to 12.47)

0.161

Air Kerma (mGy)

496.46 (330.95–842.8)

495.89 (323.15–842.8)

500.275 (331.58–823.48)

0.6403

Estimated peak skin dose (mGy)

461.18 (376.11–639.2)

460.89 (372.1–639.2)

463.14 (376.43–629.27)

0.640

6.5

6.74

<0.001

Diagnostic reference level

(Gy.cm2) 6.55

DAP = dose area product, which is also known as the kerma area product.

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Posters from JIM 2021 Giant Abdominal Aortic Aneurysm: Radiographic Features of Impending Rupture in an Atypical Presentation Aman B Williams1 and Lauren G Lax2 1. Department of Vascular Surgery, Gold Coast University Hospital, Southport, QLD, Australia; 2. Intensive Care Unit, Gold Coast University Hospital, Southport, QLD, Australia

Citation: Interventional Cardiology Review 2021;16:e22. DOI: https://doi.org/10.15420/icr.2021.16.PO11 Correspondence: Aman Berry Williams, 38 Aspen Way, Arundel, 4214 QLD, Australia. E: amanbw@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Background: Giant abdominal aortic aneurysm (GAAA) is defined as aortic diameter >100 mm – a rare variant amongst the acute aortic syndromes. Detection of new abdominal aortic aneurysms (AAAs), or those enlarging, is not uncommon; however, it is unusual to find those bigger than 70 mm and remain asymptomatic. Here, we report the subtle presentation of a 130 mm GAAA, and the radiographic features of impending rupture. Case report: An 83-year-old man presented to hospital with intractable nausea. He was highly comorbid and frail, but otherwise was haemodynamically stable and pain-free. Abdominal examination revealed a large, non-tender, pulsatile mass, confirmed to be a AAA by bedside ultrasound. CT angiogram (CTA) was undertaken, demonstrating a 130 mm infrarenal GAAA, with patchy circumferential atherosclerosis and no aortic thrombus burden (Figure 1). Given personal wishes, the patient opted for conservative antiemetic management and discharged home. The following day he presented via ambulance to the Emergency Department, profoundly shocked. Resuscitation measures provided a

Figure 1: Axial Slice from Abdominal CTA on Initial Presentation, Demonstrating the Unruptured Giant Infrarenal Abdominal Aortic Aneurysm

Measuring at a maximum diameter of 130 mm. Note the patchy appearance to the circumferential aortic calcification, and absence of intraluminal thrombus.

short period of stability, allowing for a repeat CTA. This demonstrated the GAAA had ruptured, with a large left-sided retroperitoneal haematoma displacing the abdominal viscera entirely, with surrounding fat-stranding and free-fluid (Figure 2). As per his wishes, he passed away later that day. Discussion: Medical imaging is key in decoding the urgency of a suspected unruptured AAA. Ultrasound provides rapid estimation of aortic diameter (greatest predictor of rupture); however, outside of a dedicated vascular laboratory this is limited in identifying other nuances of impending rupture. CTA is the gold-standard in AAA evaluation. Circumferential aortic calcification is important, notably checking for discontinuations, which may represent aortic wall weakness and potential future rupture sites. Luminal thrombus is a significant finding, where aortic-wall-stress studies have found increasing thrombus-rind to be protective against rupture. Contrast enhancement dissecting through aortic-thrombus is known as the hyperattenuating crescent sign, an early and specific feature of impending rupture.

Figure 2: Axial Slice from Abdominal CTA on Subsequent Presentation, Demonstrating Ruptured Giant Abdominal Aortic Aneurysm

Note the active contrast extravasation extending from the left lateral aspect of the aneurysm and resulting large left sided retroperitoneal haematoma with displacement of abdominal viscera from left-to-right.

Posters from JIM 2021 Mistral Tricuspid Regurgitation Echocardiography CoreLab Analysis Results Yan Topilsky,1 Dana Yaron2 and Meytal Bork2 1. Cardiology Division, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 2. Mitralix Ltd, Yokne’am, Israel

Citation: Interventional Cardiology Review 2021;16:e23. DOI: https://doi.org/10.15420/icr.2021.16.PO12 Correspondence: Dana Yaron and Meytal Bork, Mitralix Ltd, Yokne’am, Israel. E: dana@mitralix.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Objective: Present Echo CoreLab (Prof Topilsky) analysis short term results of all tricuspid first-in-human study Mistral device (Mitralix) performed up to October 2020.

Figure 1: The Mistral Device

Methods: Trans-thoracic echocardiography (TTE) files were sent to Echo CoreLab for analysis. Echo CoreLab was blinded to sites and results of all exams. Measurements include tricuspid regurgitation (TR) parameters and right ventricular function parameters at 1 month and 6 months follow-up. Results: 17 Mistral procedures were performed in four different centres (Germany and Israel). Results of 46 TTE exams are presented in this poster. Conclusion: The Mistral device (single or multiple devices) was seen in TTE and TR and right ventricular (RV) function parameters can be measured. It was concluded that TR and RV function parameters improved at 1 month and 6 months.

Figure 2: Mistral Procedure

Introduction Methods and Materials

Tricuspid regurgitation parameters are graded using a five-class grading scheme (mild, moderate, severe, massive, and torrential) according to the standard American Society of Echocardiography grading scheme.3 Grading of TR parameters severity (mild, moderate, severe, massive and torrential) followed recommendations given in current guidelines with consideration of qualitative parameters, semi-quantitative parameters, and quantitative parameters. The expanded grading scheme is used in order to take into account the massive and torrential grades. Cut-off values are 21 mm, 80 mm² and 75 ml for vena contracta width, EROA and Rvol by PISA, respectively, with values equal or higher indicating torrential TR. RV function was assessed using several parameters, including RV fractional area change (RV FAC), Tricuspid Annular Pane Systolic Excursion (TAPSE), right atrial volume, RV end diastolic dimension, annular diameter and tenting height.4

Results

The results are summarised in Tables 1, 2 3 and 4 and Figures 3, 4 and 5 on the following pages. 1.

Zoghbi WA, Adams D, Bonow RO,et al. Recommendations for noninvasive evaluation of native valvular regurgitation. J Am Soc Echocardiogr 2017;30:303–71. https://doi.org/10.1016/j. echo.2017.01.007; PMID: 28314623. 2. Lancellotti P, Tribouilloy C, Hagendorff A, et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: : an executive summary from the European Association of Cardiovascular Imaging. Eur

Discussion and Conclusion

Echo CoreLab analyses include 46 exams, for 17 patients, from 4 different sites at 3 time points (baseline, 1 month and 6 months). The Mistral device (single/multiple) was clearly seen in TTE in all follow ups. TR results shows improvement in 1 months follow up and durable up to 6 months follow up. The Mistral device provided, beyond substantial TR reduction, a clinically important improvement in RV function and significant RV reverse remodelling. Further studies are required to show safety and efficacy with the innovative novel Mistral device.

Heart J Cardiovasc Imaging 201;14:611–44. https://doi. org/10.1093/ehjci/jet105; PMID: 23733442. 3. Douglas PS, DeCara JM, Devereux RB, et al. Echocardiographic imaging in clinical trials: American Society of Echocardiography Standards for echocardiography core laboratories. J Am Soc Echocardiogr 2009;22:755–65. https://doi.org/10.1016/j. echo.2009.05.020; PMID: 19560654.

4. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1–39. e14. https://doi.org/10.1016/j.echo.2014.10.003; PMID: 25559473.

JIM 2021 Posters Table 1: First in Human – 1 Month Follow-up Results

Table 2: First in Human – 6 Months Follow-up Results

Table 3: EROA, Rvol and Vena Contracta Echo CoreLab Measurement Average and STD at Three Time Points Avg ± STD

Baseline (n=17)

1 Month Follow-up (n=17)

6 Month Follow-up (n=12)

EROA [cm2]

0.54 ± 0.27

0.33 ± 0.28

0.29 ± 0.18

Rvol [ml/beat]

48.2 ± 12.2

28.9 ± 15.3

26.4 ± 19.2

Vena contracta [cm]

0.91 ± 0.3

0.6 ± 0.3

0.68 ± 0.3

Table 4: Right Ventricular Function Parameters Echo CoreLab Measurement Average and STD at Three Time Points Baseline

30 Days

6 Months

RV fractional area change (n)

RV fractional area change (%)

33.1 ± 7.6

39.6 ± 8.5

42.8 ± 9.2

TAPSE (n)

TAPSE (cm)

1.66 ± 0.3

1.86 ± 0.4

1.92 ± 0.5

Right atrial volume (n)

Right atrial volume (ml)

119.7 ± 47.6

109.6 ± 53.1

99.3 ± 32.6

RV end diastolic dimension (n)

RV end diastolic dimension (cm)

4.56

4.44

4.25

Annular diameter (n)

Annular diameter (cm)

40.88 ± 4.01

37.59 ± 7.26

39.23 ± 4.07

Tenting (tethering) height (n)

Tenting (tethering) height (mm)

6.80

6.0

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JIM 2021 Posters Figure 3: Right Ventricular Function Parameters Echo CoreLab results at 1 and 6 Months Follow-up

Figure 4: All Tricuspid Regurgitation Cases

Figure 5: Echo Core Lab Results

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Coronary

Functionally Complete Coronary Revascularisation in Patients Presenting with ST-elevation MI and Multivessel Coronary Artery Disease Luigi Di Serafino , Fabio Magliulo

and Giovanni Esposito

Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy

Abstract

Up to half of patients undergoing primary percutaneous coronary intervention of a culprit stenosis in the context of the ST-elevation MI may present with multivessel disease. The presence of non-culprit stenoses have been shown to affect the outcomes of these patients, and the results of the more recent randomised trials highlight the importance of complete coronary revascularisation. In this paper, the authors review the main trials published on the topic and discuss tools for the assessment of non-culprit stenoses, while considering the right time for carrying out a complete coronary revascularisation.

Keywords

ST-elevation MI, non-culprit stenosis, complete revascularisation, fractional flow reserve, quantitative flow ratio Disclosure: The authors have no conflicts of interest to declare. Received: 14 September 2020 Accepted: 26 April 2021 Citation: Interventional Cardiology Review 2021;16:e24. DOI: https://doi.org/10.15420/icr.2020.28 Correspondence: Luigi Di Serafino, Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini 5, 80131, Naples, Italy. E: luigi.diserafino@unina.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Multivessel coronary artery disease (MVD) occurs in about half of patients presenting with ST-elevation MI (STEMI) and undergoing primary percutaneous coronary intervention (PCI), and this affects both in-hospital and long-term clinical outcomes.1,2 While treating the infarct-related artery (IRA) is obviously recommended, current evidence supports revascularisation of residual significant nonculprit coronary artery lesions (NCLs). However, the ideal tool for the assessment of such residual stenoses, as well as the best time for their revascularisation remain controversial, so incomplete coronary revascularisation after primary PCI continues.

(2.5 ± 1.4 years), 70 (32.7%) patients had experienced at least one major cardiac adverse event (MACE): 42 (50.0%) in the culprit-only revascularisation group; 13 (20.0%) in the staged revascularisation group; and 15 (23.1%) in the CR group (p<0.001).8 The incidence of inhospital death, repeat revascularisation and rehospitalisation was significantly higher in the culprit-only revascularisation group, whereas there was no significant difference in terms of reinfarction between the three groups, suggesting that culprit vessel-only PCI is associated with a higher rate of clinical events than multivessel treatment.8

Recent findings suggest that CR in patients presenting with STEMI and MVD is associated with a better clinical outcome than primary PCI of the IRA only, regardless of whether CR was carried out during the index procedure, the index hospitalisation or during a later readmission (Table 1).3–7

In the PRAMI trial, 465 patients presenting with STEMI undergoing primary PCI of the IRA were randomised to either preventive PCI (234 patients) or no preventive PCI (231 patients).3 Patients were eligible after primary PCI if the IRA had been successfully treated and there was a residual stenosis visually estimated to be ≥50% in at least one coronary artery other than the IRA. Recruitment was stopped early after a recommendation from the data and safety monitoring committee based on a highly significant between-group difference (p<0.001) in terms of incidence of the primary endpoint favouring preventive PCI. At a median of 23 months follow-up, the primary outcome, a composite of cardiac death, non-fatal MI or recurrent angina, occurred in 21 patients (9%) in the preventive PCI group and 53 (23%) in the group receiving PCI of the IRA only.3

In a small randomised clinical study of 214 patients presenting with STEMI, Politi et al. divided subjects into three groups: PCI of the IRA only (culprit-only revascularisation, n=84); staged revascularisation of the NCLs (n=65); and simultaneous treatment of NCLs (CR, n=65). Residual stenoses were considered angiographically significant if the diameter of the stenosis (DS) was visually estimated to be >70%.8 At the follow-up

In the DANAMI-3-PRIMULTI trial, performed at two Danish centres, 627 STEMI patients were randomised to no further invasive treatment after primary PCI of the IRA (n=313) or fractional flow reserve (FFR)-guided complete revascularisation (n=314).5 In this study, coronary lesions with a visually estimated DS >90% were considered angiographically significant, while stenoses of 50–90% underwent FFR assessment. At a median

In this review, we discuss the current evidence about the benefits of complete revascularisation (CR) in patients presenting with STEMI and MVD, and examine tools for the assessment of NCLs.

Complete Coronary Revascularisation versus Infarct-related Artery-only PCI

Non-culprit Lesion PCI in STEMI Patients Table 1: Randomised Controlled Trials Comparing Complete Versus Culprit-only Percutaneous Coronary Intervention in ST-elevation MI Patients Definition of Significant Stenosis

Study

Intervention

Control

Primary Outcome

Results

Politi et al.8

PCI of NCLs during either the index (CR; n=65) or a staged procedure (SR; n=65)

PCI of the culprit lesion only (COR; n=84)

Visual estimation Angio-guided NCL PCI: DS >70%

Composite of cardiac death Primary outcome non-cardiac death, in-hospital CR: 23% versus SR: 13% versus death, reinfarction, COR: 50% (Kaplan-Meier rehospitalisation ACS and new analysis p=0.012) revascularisation

PRAMI3

PCI of NCLs during the index procedure (CR; n=234)

PCI of the culprit lesion only (CL; n=231)

Visual estimation Angio-guided NCL PCI: DS >50%

Composite of cardiac death, non-fatal MI and refractory angina

CvLPRIT4

PCI of NCLs during the index procedure or index admission (CR; n=138)

PCI of the culprit lesion only (CL; n=139)

Visual estimation Angio-guided NCL PCI: DS >70% in one view or DS >50% in two views

Composite of all-cause death, Primary outcome recurrent MI, heart failure and CR: 10.0% versus CL: 21.2% (HR ischaemia-driven 0.45; 95% CI: [0.24–0.84]) revascularisation

DANAMI-3PRIMULTI5

PCI of NCLs during the index admission (CR; n=314)

PCI of the culprit lesion only (CL, n=313)

Visual estimation Angio-guided NCL PCI: DS >90% FFR-guided NCL PCI: DS >50% and FFR ≤0.80

Composite of all-cause death, Primary outcome reinfarction and ischaemia- CR: 13% versus CL: 22% (HR: driven revascularisation 0.56; 95% CI [0.38–0.83]

COMPARE ACUTE9

PCI of NCLs during the index procedure or index admission (CR; n=295)

PCI of the culprit lesion only (CL; n=590)

Quantitative coronary angiography FFR-guided PCI: DS >50% and FFR ≤0.80

Composite of all-cause death, Primary outcome non-fatal MI, any CR: 7.8% versus CL: 20.5% revascularisation and (HR: 0.35; 95% CI: 0.22–0.55 cerebrovascular events

COMPLETE7

PCI of NCLs during the index admission or staged (CR; n=2,016)

PCI of the culprit lesion only (CL; n=2025)

Visual estimation Angio-guided PCI: DS >70% FFR-guided PCI: DS 50%–69% and FFR ≤0.80

Composite of cardiovascular death and MI; and composite of cardiovascular death, MI and ischaemia-driven revascularisation

Primary outcome CR: 9% versus CL: 23% (HR 0.35; 95% CI [0.21–0.58])

Primary outcome 1 CR: 7.8% versus CL: 10.5% HR 0.74; 95% CI: 0.60–0.91 Primary outcome 2 CR: 8.9% versus CL: 16.7% (HR 0.51; 95% CI [0.43–0.61])

ACS = acute coronary syndrome; CL = culprit lesion; COR = culprit-only revascularisation; CR = complete revascularisation; DS = diameter of stenosis; FFR = fractional flow reserve; NCL= non-culprit lesion; PCI = percutaneous coronary intervention; SR = staged revascularisation.

follow-up of 27 months, the primary endpoint (a composite of all-cause mortality, reinfarction or ischaemia-driven revascularisation of NCLs) was met in 68 (22%) patients undergoing PCI of the culprit lesion only and in 40 (13%) patients assigned to complete coronary revascularisation (HR 0.56; 95% CI [0.38–0.83]; p=0.004).5 Of note, CR resulted in a 69% risk reduction for repeat revascularisations. No significant difference in cardiac death between the two groups was observed, but the need for both urgent and non-urgent PCI of NCLs was significantly lower in the complete revascularisation group.5 In the CvLPRIT trial, 296 patients in seven UK centres were randomised to either in-hospital complete revascularisation (n=150) or IRA-only revascularisation (n=146), with the relevance of residual coronary stenoses assessed by angiographic evaluation.4 CR was performed either at the time of primary PCI or before hospital discharge.4 Residual stenoses were considered angiographically significant if the DS was estimated visually to be >70% (in one view) or >50% (in two views). At 1-year follow up, MACE was significantly lower in the CR group (10.0%) than in the IRA-only group (21.2%; HR: 0.45; 95% CI [0.24–0.84]; p=0.009).4 Cardiovascular mortality was also numerically lower in the CR group. Moreover, a trend towards a lower MACE rate was also found in patients undergoing CR during the index procedure than in those having a staged procedure.4 In the COMPARE-ACUTE trial, 885 patients presenting with STEMI and MVD who underwent primary PCI were assigned, at a 1:2 ratio, to FFRguided CR (n=295) or to medical therapy (n=590).9 Residual stenoses were considered angiographically suitable for FFR assessment if their DS was >50% by a visual estimation or quantitative angiography. The primary

outcome occurred in 23 patients in the CR group and in 121 patients in the IRA-only PCI (HR 0.35; 95% CI [0.22–0.55]; p<0.001).9 This difference was driven mainly by a significant reduction in risk of needing new revascularisations. More recently, the COMPLETE trial showed that, among patients with STEMI and MVD, CR was superior to IRA-only PCI in reducing the risk of cardiovascular hard endpoints at a median follow-up of 3 years.7 Residual stenoses were considered significant if, by visual estimation, DS was >70% or FFR was ≤0.80 in cases of stenoses of 50–69%. Furthermore, in this study, the investigators had to specify if they intended to perform PCI of non-culprit stenosis, either during the index procedure or 45 days later, should the patient be allocated to complete revascularisation; this allowed the investigators to evaluate whether the treatment effect of complete revascularisation versus culprit-lesion only PCI differed depending on the intended timing of non-culprit PCI. In patients who were intended to undergo PCI during the index hospitalisation, the incidence of the two primary outcomes (cardiovascular death or MI; or cardiovascular death, MI or ischaemia-driven revascularisation) were 2.7% and 3.0% per year, respectively, in patients randomised to complete revascularisation, compared to 3.5% and 6.6% per year in those undergoing culprit-lesion-only PCI.7 The p-values for interaction for the effect of timing on the two outcomes were p=0.62 and p=0.27, respectively, suggesting a benefit of CR regardless of whether non-culprit PCI was performed during the index hospitalisation or within 45 days after randomisation. The authors explain this benefit was the result of well-treated patients with evidence-based therapies, including

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Non-culprit Lesion PCI in STEMI Patients Figure 1: Stenosis After Percutaneous Coronary Intervention

Patient presenting with ST-elevation-MI and multivessel disease. A: ECG of a patient presenting with typical chest pain in the emergency room, showing the ST-segment elevation in the anterior leads and Q waves in V1–V4. Within 45 minutes, the patient was transferred to the catheterisation laboratory and underwent coronary angiography (B), which showed the total acute occlusion of the left anterior descending artery; this was rapidly treated with stent implantation and the flow was completely restored (C). However, after percutaneous coronary intervention, angiography of the right coronary artery showed an intermediate stenosis at both mid and distal segments (D).

dual antiplatelet therapy with aspirin and a P2Y12 inhibitor, with the latter being either ticagrelor or prasugrel in the vast majority of the patients. This might have protected against early thrombotic events related to nonculprit stenosis before staged PCI. Finally, three meta-analyses, mainly based on the cited trials, found CR was associated with a lower risk of repeat revascularisation, non-fatal MI and cardiovascular mortality compared to culprit-only PCI.10–12 Accordingly, both the European and the American guidelines now recommend PCI of NCLs should be considered in patients with STEMI and MVD before hospital discharge, either at the time of the primary PCI or in a staged procedure.13–15 However, the optimal strategy for the assessment of NCLs as well as the best timing for obtaining complete revascularisation are still matter of discussion.

Invasive Evaluation of Non-culprit Lesions

In patients presenting with STEMI when NCLs are present (Figure 1), different clinical strategies can be considered. After the treatment of the IRA, one option is initial optimal medical therapy, with further revascularisation driven by symptom recurrence. Alternatively, the decision about the need for NCL revascularisation may be based on either angiographic or functional lesion assessment (Figure 2). In all cases, NCLs should be assessed during the index procedure or within a few days of the index hospitalisation, as current guidelines suggest.13–15

Pitfalls of Angiographic Assessment of Non-culprit Lesions

During the acute phase, severity of NCLs may be overestimated by approximately 10%, especially if visual evaluation is performed by operators with low FFR experience.16–18 Consequently, angiographyguided NCL PCI in the acute setting might lead to functionally nonsignificant stenoses being treated.

While the PRAMI and the CvLPRIT trials were based on angiographic definition of the significant residual stenosis (DS >50%), and the DANAMI3-PRIMULTI and COMPARE ACUTE trials were based on haemodynamic assessment of residual coronary artery stenosis at the FFR evaluation (Table 1).3–5,9 However, in the COMPLETE trial, while residual stenoses with a DS >70% were considered angiographically significant, those ones with a DS of 50–70% (<1%) were functionally assessed with the FFR. Of note, when angiographic NCL evaluation was supplemented with FFR, 31% of patients randomised to CR in the DANAMI-3-PRIMULTI and 44% in the COMPARE-ACUTE trial did not need further PCI.5,9 This demonstrates angiographic evaluation of NCLs overestimates their ischaemic potential. It also showed that if the functional assessment of NCLs is postponed until a few days after the acute setting, the risk of performing a useless invasive procedure because a negative FFR value is found ranges between 30% and 50% of cases. Furthermore, functionally non-significant NCLs may have been treated in the angiography-guided PRAMI, CvLPRIT and COMPLETE trials, suggesting that physiology would have led to the same benefit of CR although with less PCI.3,4,7 This is in line with the evidence that in patients with stable angina undergoing FFR-guided PCI, the residual angiographic SYNTAX score (rSS) was not predictive of adverse clinical outcome; this suggests that the functional significance of a coronary lesion is definitively the most important feature for predicting future adverse cardiac events, more so than angiographic severity, and supporting the concept of functionally complete coronary revascularisation.19 Because of the frequent mismatch between the angiographic and haemodynamic severities of coronary stenoses, invasive functional evaluation, even in the setting of ACS, should be considered for all residual lesions with a DS of 50–90%, as recommended by the European guidelines for the diagnosis and management of chronic coronary syndromes.20,21

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Non-culprit Lesion PCI in STEMI Patients Figure 2: Angiographic and Functional Evaluation of a Right Coronary Artery Stenosis

In the acute setting, after successful primary percutaneous coronary intervention of the left anterior descending artery, two intermediate and serial stenoses of the right coronary artery at the mid (white arrow) and distal (black arrow) segment were assessed. At the initial visual estimation, the diameter of both stenoses was >50%, while at quantitative coronary angiography assessment, they were <50%. According to the PRAMI study, the visual assessment would have been enough to support percutaneous revascularisation of the right coronary artery.3 However, bearing in mind that angiographic assessment may result in ischaemic potential being overestimated, particularly in the acute phase of a ST-elevation MI, and to reduce the risk of performing unnecessary percutaneous coronary intervention, the residual stenosis was also assessed with QFR; the lesion was found to be functionally non-significant (QFR: 0.92) so suitable for medical therapy. This was confirmed by a FFR assessment, performed during the same procedure, which found a negative value (FFR=0.85). DS = diameter of stenosis; FFR = fractional flow reserve; Pa = coronary pressure; Pd = distal coronary pressure; QCA = quantitative coronary angiography; QFR = quantitative flow ratio.

Functional Assessment of Non-culprit Lesions Using Pressure Wire

FFR is the gold standard for the invasive assessment of the ischaemic potential of a coronary artery stenosis. It is defined as the ratio between the mean distal coronary pressure and the mean aortic pressure during maximal hyperaemia and it has been shown to be useful in several clinical and anatomic contexts.22–26 Recently, a number of non-hyperaemic indices have been introduced and, as these are favoured because of a high correlation with the FFR but have the disadvantage of the need to induce maximal hyperaemia, they are more often used in the catheterisation laboratory.27,28 In the context of STEMI, functional assessment of the culprit vessel is not indicated because the dynamic changes of microcirculatory dysfunction are assessed by the index of microcirculatory resistance, leading to possible underestimation of the ischaemic potential of residual stenosis.29,30 However, a large amount of data exists for the use of such tools for the assessment of NCLs, even though most of the current evidence supporting their use has been derived from patients presenting with chronic coronary syndrome. However, concerns have arisen in the past about the use of FFR for the assessment of NCLs in the context of ACS, particularly in the very acute phase. In fact, it has been thought that transient coronary microcirculation dysfunction might be detected even in myocardial territories supplied by non-culprit arteries, probably due to increased neurohumoral activation and/or extravascular compression secondary to myocardial oedema.31–35 In this clinical setting, temporary impairment of the microcirculation subtended by an equivocal stenosis would lead to the ischaemic potential of the coronary lesion being underestimated.

index procedure and after one month in patients presenting with ACS.35 Similarly, in an elegant Yorkshire pig model, Lee et al. showed that local microvascular damage induced by selective intracoronary injection of microspheres increased both the FFR and the index of microcirculatory resistance, while both remained stable in the other vessels.37 In the Wave study, Musto and colleagues showed both the FFR and instantaneous wave-free ratio (iFR) values of NCLs did not significantly change between the index and staged procedure.38 Finally, Mejía-Rentería et al. also support the use of FFR to assess NCLs during the subacute phase of MI; they also observed that, unlike the hyperaemic flow, which is preserved during the subacute phase of MI, the resting coronary flow is increased, which may have implications for the use of non-hyperaemic indices for the assessment of NCLs.39 In the iSTEMI study, the iFR value of NCLs increased by a median of 0.01 from the index procedure when re-evaluation was performed within 16 days but rose by a median of 0.03 when re-evaluation was performed >16 days after primary PCI of the culprit stenosis.40 Taken together, these studies suggest that deferring NCL revascularisation based on both the FFR and the iFR is possible even during the acute phase of a STEMI. It should be borne in mind that the ischaemic potential of residual stenosis might be overestimated when assessed by nonhyperaemic indexes.

In another study, van der Hoeven et al. showed that FFR values measured for the assessment of NCLs during the index procedure were significantly higher than those measured at 30 days’ follow-up, with a mean decrease of 0.03 units; this was particularly so in patients with larger infarcts, suggesting that the ischaemic potential of NCLs might be underestimated if FFR is used during the acute setting.36

While the clinical relevance of acute iFR-guided PCI of NCLs is being evaluated in the iMODERN trial (NCT03298659), the benefits of deferring PCI for NCLs based on the FFR measurement have already been demonstrated in previously discussed large, randomised trials.5–9 In addition, in a recent sub-analysis of three trials (FAME, FAMOUS-NSTEMI and DANAMI-3-PRIMULTI), a total of 547 patients presenting with ACS (271 patients with non-ST-elevation MI and 276 patients with STEMI) underwent FFR-guided functionally complete coronary revascularisation.41 Patients with and without MACE at 2-year follow-up had a similar rSS after PCI (rSS 7.2 ± 5.5 versus 6.6 ± 5.9; p=0.23), and a Kaplan-Meier curve analysis showed a similar incidence of MACE regardless of rSS subgroup (p=0.54).41 Therefore, even in the context of ACS, the extent of residual angiographically significant disease is not a predictor of clinical events.

However, Ntalianis et al. found there was no significant difference between FFR values measured for the assessment of NCLs during the

Particular attention should be paid to this when with caring for elderly patients presenting with STEMI and MVD, since the benefits of complete

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Non-culprit Lesion PCI in STEMI Patients revascularisation, whether guided by the FFR or not, remain a matter of discussion.

basis of the ADDED index, rather than the visually estimated DS, is associated with a favourable clinical outcome.50

A recent sub-analysis from the DANAMI-3-PRIMULTI trial showed no significant differences in the incidence of the primary endpoint in elderly patients (aged ≥75 years) randomised to culprit-only or FFR-guided complete revascularisation.42 However, in the main study, fewer than 20% of patients were aged ≥75 years, so the question of whether FFR-guided complete revascularisation is effective also in this group has still to be answered. In the FIRE trial, the investigators aim to provide robust evidence on whether a specific revascularisation strategy should be applied to elderly patients presenting with MI and MVD to improve their clinical outcomes.43

Similarly, the DILEMMA score takes into account the minimal lumen diameter, the lesion length and BARI (Bypass Angioplasty Revascularisation Investigation) Myocardial Jeopardy Index, and it was found to have a good correlation with FFR and a discrete accuracy in predicting significant FFR values.51

Wire-free Functional Evaluation Quantitative Flow Ratio

Quantitative flow ratio (QFR) is a novel angiography-based tool for the functional assessment of coronary artery stenoses. It has been shown to correlate with FFR, and was validated in the FAVOR and FAVOR II studies.44,45 It is based on 3D vessel reconstructions derived from angiography and the contrast flow velocity estimated by the frame count. Two small studies assessed the predictive value of the QFR compared with FFR to identify functionally significant NCLs. In a sub-analysis of the iSTEMI study, acute QFR showed a good diagnostic performance with both staged QFR and staged FFR as references, and a moderate diagnostic performance with staged iFR as the reference.46 Spitaleri et al. published a proof-of-concept study about the application of QFR for the assessment of NCLs in patients presenting with STEMI.47 They showed an agreement between the QFR values assessed during the index (acute) and staged (3–4 days later) procedures. In addition, in a different cohort of patients, the authors found a good correlation between the FFR and QFR values of NCLs. Finally, in another cohort of patients, they showed that those with a NCL presenting with a QFR value ≤0.80 were at a higher risk of patient-oriented cardiac events (HR 2.3; 95% CI [1.2–4.5]; p=0.01).

Such scores could help operators to discriminate functionally significant residual coronary stenosis in patients presenting with STEMI and MVD or be used to identify patients who can be safely discharged home, avoiding useless PCI or adjunctive invasive or non-invasive procedures to assess the ischaemic potential of non-culprit coronary stenosis. However, such roles have not been investigated yet.

Intracoronary Imaging to Guide Revascularisation of Non-culprit Lesions

Intracoronary imaging has also been proposed as tool for detecting significant stenosis, namely those with the features of high-risk vulnerable plaques and significantly associated with the occurrence of acute coronary syndromes (Table 2).52 Intravascular ultrasound (IVUS) is a well-established imaging technique used in the assessment of coronary plaque features. Beyond the possibility to estimate both vessel size and plaque burden, virtual histology IVUS allows operators to identify thin-cap fibroatheroma (TCFA), fibrotic plaque and fibrocalcific plaque. In the PROSPECT study, the presence of a plaque burden of ≥70%, a TCFA and a minimal lumen area ≤4 mm2 have been suggested as independent predictors of MACE related to NCLs in patients presenting with ACS.53 Near-infrared spectroscopy has been also proposed to detect lipid-rich plaques. In the Lipid-Rich Plaque study, the risk of non-culprit-related MACE at two years increased of 18% for each 100-unit increase in maximum lipid core burden index.54

Similarly, in the QIMERA study, QFR reassessment during a staged procedure reduced the number of significant NCLs as assessed by angiography and showed good agreement with FFR and, all patients with a QFR-negative (QFR values ≥0.82) stenosis during the index procedure remained nonsignificant at a staged assessment.48 However, 3D-QFR requires training, might be time consuming and, at least in part, is operator-dependent, which means that the assessment may be different depending on the operator who analyses the vessel (because of his experience and skills).

Optical coherence tomography (OCT) is a light-based imaging technique and is currently the most reliable imaging modality for TCFA detection. In the Massachusetts General Hospital OCT registry, which includes more than 1,400 patients (40% ACS), the presence of a non-culprit, lipid-rich plaque was independently associated with an increased risk of MACE related to non-culprit stenosis at 2 years.55 In the CLIMA study of >500 patients with ACS, a minimal lumen area of <3.5mm2, a fibrous cap thickness <75 mm, a lipid arc circumferential extension >180° and OCT-defined macrophage infiltration were all associated with an increased risk of MACE.56

Other Angiographic Scores

In a OCT sub-study of the COMPLETE trial, among STEMI patients with MVD, it was found that half of patients had non-culprit lesions containing TCFA, which was more often detected in angiographic significant stenosis (DS >70% at visual estimation) than in non-obstructive lesions.57 However, it should be underlined that both OCT and IVUS-derived indexes of plaque vulnerability have a high negative predictive value for MACE but only a low positive predictive value, which limit their clinical applicability.53,56

Recently, two angiographic tools, the Angiography-DeriveD hEmoDynamic index (ADDED index) and the DILEMMA score, have been shown to predict the FFR value. The ADDED index is defined as the ratio between the Duke Jeopardy score, which accounts for the myocardium subtended by the coronary artery stenosis and the minimal lumen diameter acquired by quantitative coronary analysis.49 With a cut-off value of 2.23, the ADDED index shows good diagnostic performance for predicting a positive or negative FFR value, with overall accuracy, sensitivity and specificity of 86%, 94% and 82%, respectively.49 In patients presenting with STEMI and MVD, it has recently been shown that deferring treatment of residual stenosis on the

Non-invasive Assessment of Non-culprit Lesions

Before FFR was introduced, functional evaluation of intermediate coronary artery disease relied on non-invasive tests to identify the presence of stress-inducible myocardial ischaemia. Among them, exercise ECG can be considered as their forefather. Exercise ECG can be carried

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Non-culprit Lesion PCI in STEMI Patients Table 2: Intracoronary Imaging for the Assessment of Non-culprit Lesions Study

Imaging Technique

Plaque Features

PROSPECT53

697 ACS

IVUS

Thin cap fibroatheroma, plaque burden ≥70%, MLA ≤4 mm2

Lipid-Rich Plaque study

1,271 (53.7% ACS)

NIRS

Lipid-rich plaque

Massachusetts General Hospital registry55

1,474 (39% ACS)

OCT

Lipid-rich plaque

CLIMA study56

1,003 (53.4% ACS)

OCT

MLA <3.5 mm2, fibrous cap thickness <75 mm, lipid arc circumferential extension >180º, presence of macrophages

ACS = acute coronary syndrome; IVUS = intravascular ultrasound; MLA = minimum lumen area; NIRS = near-infrared spectroscopy; OCT = optical coherence tomography.

out 3–5 days after an uncomplicated ACS according to the American College of Cardiology and the American Heart Association guidelines (even though it should be submaximal).58 The evidence of a stress test at an acceptable cardiovascular workload (five or more metabolic equivalents) without any ECG changes, angina, hypotension, significant ST-segment depression or frequent ventricular premature contractions may show a post-MI patient is at a low risk of recurrent cardiac events; however, there are consistent limitations to using exercise ECG to assess the functional relevance of residual coronary disease. First, exercise ECG does not have spatial resolution to correctly identify myocardial ischaemia, especially in patients with MVD; in addition, changes to the ECG at rest after MI might decrease the sensibility and the predictive value of the test. Dobutamine stress echocardiography has been proven to be safe when performed 5 days after MI.59 Previous studies have shown that stress echocardiography might be an efficient tool to detect the presence of myocardial ischaemia, including in myocardial territories not supplied by the culprit artery in patients with MVD.60 Coronary flow velocity reserve (CFVR) by transthoracic Doppler echocardiographic imaging might be also useful in the assessment of non-culprit coronary artery stenosis. Tesic et al. enrolled 230 patients with residual intermediate (50%–70%) stenosis of the non-infarct-related arteries, in whom CFVR was performed within 7 days of primary PCI. The authors found that deferring patients with intermediate residual stenosis with a CFVR >2 was safe and associated with excellent long-term clinical outcomes. However, this tool is particularly affected by some limitations due to the acoustic window of the patients and the feasibility of the technique to assess flow in different coronary arteries. The evaluation of CFVR is more feasible in the left anterior descending artery and right coronary artery than the left circumflex artery.61 Similarly, quantitative myocardial single photon emission CT (SPECT) has been used largely to detect residual myocardial ischaemia after acute MI.62 Stress echocardiography and myocardial SPECT are equally accurate for detecting MVD early after acute MI.60 However, unlike with the FFR-guided strategy, there are no studies evaluating the prognostic impact of a non-invasive, imaging-based strategy to guide myocardial revascularisation of residual non-culprit coronary artery disease in patients with STEMI.63 The same applies to perfusion cardiac MRI. 1.

Sorajja P, Gersh BJ, Cox DA, et al. Impact of multivessel disease on reperfusion success and clinical outcomes in patients undergoing primary percutaneous coronary

FFR derived from computed coronary angiography (FFR-CT) deserves the final mention in this setting. Computation of the FFR from standard acquired coronary CT angiography datasets has recently been developed. The diagnostic performance of FFR-CT in identifying functional significant stenosis using the FFR as the standard of reference is high and superior to anatomical interpretation in patients with stable angina; in addition, its application for the evaluation of NCLs in patients presenting with STEMI has recently been evaluated in a prospective, single centre study where patients undergoing primary PCI with at least one equivocal stenosis in a non-culprit vessel were subjected to coronary CTA after 1 month.64 Using computational fluid dynamics principles, coronary blood flow and pressures were computed under simulated hyperaemic conditions; lesion-specific ischaemia was defined as FFR-CT <0.80 as in previous studies. However, in this study, the overall diagnostic performance of FFR-CT for staged detection of functional significant NCLs appeared to be modest.64 Cardiac MRI might also be considered to evaluate patients with suspected obstructive coronary artery disease. Cardiac MRI does not expose patients to ionising radiation and allows high-resolution imaging to be obtained. It is also possible to quantify myocardial blood flow in both relative and absolute terms.65,66 In a sub-study of the REDUCE-MVI trial, Everaars et al. found a moderate agreement between CMR and FFR for the assessment of non-culprit stenosis in patients presenting with STEMI and MVD. However, the sample size was limited and mainly underpowered for this purpose, so randomised trials would be useful for supporting this tool for the assessment of non-culprit stenosis in the setting of ACS.67,68

Conclusion

The correct management of residual coronary artery disease in patients with STEMI and MVD undergoing primary PCI remains a concern. Issues remain regarding the correct timing and guiding criteria for interventions. The introduction of FFR together with the concept of functionally complete coronary revascularisation is surely a critical innovation. However, functional measures, such as the FFR and/or its surrogates should not completely supplant clinical judgement. Lesion vulnerability, patient comorbidities, size of ischaemic territory, ability to comply with dual antiplatelet therapy and risk of contrastinduced kidney injury are only some of the issues that should be considered when pursuing complete revascularisation. Larger studies, such as FULL REVASC (NCT02862119) and FRAME-AMI (NCT02715518), will add further knowledge to this complex and interesting field.

intervention for acute myocardial infarction. Eur Heart J 2007;28:1709–16. https://doi.org/10.1093/eurheartj/ehm184; PMID: 17556348.

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2. van der Schaaf RJ, Timmer JR, Ottervanger JP, et al. Longterm impact of multivessel disease on cause-specific mortality after ST elevation myocardial infarction treated

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Editorial

Advanced Cardiac Interventions During Pregnancy: A Personal Perspective Angela HEM Maas Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands

Disclosures: The author has no conflicts of interest to declare. Received: 7 April 2020 Accepted: 11 May 2020 Citation: Interventional Cardiology 2021;16:e25. DOI: https://doi.org/10.15420/icr.2020.12 Correspondence: Angela HEM Maas, Department of Cardiology, Radboud University Medical Center, PO Box 9101, Route 616, 6500 HB Nijmegen, the Netherlands. E: angela.maas@radboudumc.nl Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In one of my worst ever night shifts, I witnessed a 32-year-old pregnant woman dying while her first toddler was sitting on her bed. She died of heart failure due to a spontaneous coronary artery dissection (pSCAD) with a retrograde dissection of the whole left coronary artery. Another woman I will never forget was a mother of seven with a severe peripartum cardiomyopathy during her eighth pregnancy. She barely survived, and we managed to convince the religious couple to undergo sterilisation simultaneously with her caesarean section. Distressing experiences such as these require the courage of obstetricians alongside good collaboration with (interventional) cardiologists and other medical specialists. Severe cardiac problems during pregnancy and after delivery account for the majority of pregnancy-related maternal deaths. Recent findings of a UK cohort of 79 pregnant women with pre-existing ischaemic heart disease (IHD), reported a rate of adverse cardiac events of 6.6%, without any maternal deaths.1 However, the risk of adverse obstetric and neonatal events was greater, with rates of pre-eclampsia, preterm delivery and small for gestational age of 14%, 25% and 25%, respectively. Foetal risk may therefore be even higher than maternal risk in women with known IHD. In this special focus issue, Khaing et al. describe in their review that the risk of acute coronary syndrome (ACS) increases by three- to fourfold during pregnancy, especially in women aged >40 years.2 Although there is no evidence that in vitro fertilisation affects this risk, it is important to note that >90% of ACS in pregnancy occurs in women without prior IHD and that a coronary angiogram is done in fewer than half of all cases of ACS. In young women it is more important than ever to correctly assess 1. Cauldwell M, Steer PJ, von Klemperer K, et al. Maternal and neonatal outcomes in women with history of coronary artery disease. Heart 2020;106:380–6. https://doi.org/10.1136/ heartjnl-2019-315325; PMID: 31533991. 2. Khaing PH, Buchanan GL, Kunadian V. Diagnostic angiograms and percutaneous coronary interventions in pregnancy. Interv Cardiol 2020;15:e04. https://doi. org/10.15420/icr.2020.02; PMID: 32536975.

the underlying pathophysiology to be able to provide the most appropriate treatment advice. As many young women with ACS in pregnancy present with MI with non-obstructed coronary arteries, of which a quarter are because of pSCAD, a percutaneous coronary intervention (PCI) following angiography is often not needed or indicated.3 However, it is important to note that pregnancy itself is not a contraindication for PCI, and as a lifesaving procedure it should be performed when necessary.4 Prior unknown rheumatic valve disease may become apparent for the first time during pregnancy. For instance, mitral stenosis can cause AF with serious haemodynamic changes that need intervention during gestation. Fraccaro et al. describe interventional options during pregnancy in mitral stenosis and other serious valvular diseases.5 Although in the ideal world pre-pregnancy counselling and therapy is advised, an acute intervention during pregnancy may be needed. This certainly may be the case for immigrant women and refugees who did not have the opportunity to be screened earlier. The fast-growing experience of the interventional cardiologist in percutaneous valve procedures is of great advantage for successful and safe interventions during pregnancy, which are usually preferred over surgery. Thinking back to my own experiences with pregnant women with severe cardiac problems, it is important to realise that if you save a mother, you also save the whole family. Furthermore, in Western countries we have a moral obligation to share our growing experience in modern invasive cardiology techniques with our colleagues in less well-equipped countries to help save women’s lives.

3. Adlam D, Alfonso F, Maas A, Vrints C. European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection. Eur Heart J 2018;39:3353–68. https://doi. org/10.1093/eurheartj/ehy080; PMID: 29481627. 4. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J 2018;39:3165–

241. https://doi.org/10.1093/eurheartj/ehy340; PMID: 30165544. 5. Fraccaro C, Tence N, Masiero G, Karam N. Management of valvular disease during pregnancy: the evolving role of percutaneous treatment. Interv Cardiol 2020;15:10. https://doi.org/10.15420/icr.2020.06; PMID: 32905129.

Structural

Patient-specific Computer Simulation: An Emerging Technology for Guiding the Transcatheter Treatment of Patients with Bicuspid Aortic Valve Cameron Dowling ,1 Robert Gooley,1 Liam McCormick,1 Sami Firoozi2 and Stephen J Brecker2 1. MonashHeart, Monash Health and Monash Cardiovascular Research Centre, Monash University, Melbourne, Australia; 2. Cardiology Clinical Academic Group, St George’s, University of London and St George’s University Hospitals NHS Foundation Trust, London, UK

Abstract

Transcatheter aortic valve implantation (TAVI) is increasingly being used to treat younger, lower-risk patients, many of whom have bicuspid aortic valve (BAV). As TAVI begins to enter these younger patient cohorts, it is critical that clinical outcomes from TAVI in BAV are matched to those achieved by surgery. Therefore, the identification of patients who, on an anatomical basis, may not be suitable for TAVI, would be desirable. Furthermore, clinical outcomes of TAVI in BAV might be improved through improved transcatheter heart valve sizing and positioning. One potential solution to these challenges is patient-specific computer simulation. This review presents the methodology and clinical evidence surrounding patient-specific computer simulation of TAVI in BAV.

Keywords

Aortic valve stenosis, bicuspid aortic valve, computer simulation, finite element analysis, transcatheter aortic valve replacement, heart valve prosthesis implantation Disclosure: CD has received grants from Medtronic, outside the submitted work. RG has received personal fees from Boston Scientific, outside the submitted work. SJB has received grants and personal fees from Medtronic, outside the submitted work. All other authors have no conflicts of interest to declare. Funding: This study is part of a project that has received funding from the EU’s Horizon 2020 research and innovation programme under grant agreement No 945698. Acknowledgement: The authors thank Tim Dezutter for his assistance in preparing the animation. Received: 8 March 2021 Accepted: 19 July 2021 Citation: Interventional Cardiology 2021;16:e26. DOI: https://doi.org/10.15420/icr.2021.09 Correspondence: Cameron Dowling, MonashHeart, 246 Clayton Rd, Clayton, VIC 3168, Australia. E: cameron.dowling@monashhealth.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve implantation (TAVI) has been demonstrated in randomised trials to be associated with a lower risk of death and disabling stroke compared with surgery.1 Therefore, it is likely that TAVI will increasingly become the preferred treatment modality for most patients with symptomatic severe aortic stenosis, regardless of baseline surgical risk. However, as TAVI begins to enter younger, lower-risk cohorts, the prevalence of bicuspid aortic valve (BAV) will increase, and it is important that clinicians recognise that this patient subset was excluded from all clinical trials comparing TAVI and surgery.2 Although clinical outcomes of TAVI in BAV have improved with newer generation devices, the incidence of paravalvular regurgitation and of conduction disturbance remains higher than with surgery, and both of these complications have been associated with adverse long-term outcomes.3–6 Therefore, in the absence of randomised data directly comparing these two treatment modalities, careful patient selection by the Heart Team, based on clinical and, perhaps more importantly, anatomical characteristics, must remain paramount. Furthermore, optimising transcatheter heart valve (THV) sizing and positioning within bicuspid anatomy remains an important consideration. With this as a background, one potential solution to the challenges of TAVI in BAV is patient-specific computer simulation. In this review, we discuss

how patient-specific computer simulation may be used to guide the transcatheter treatment of patients with BAV.

Patient-specific Computer Simulation

Patient-specific computer simulation is a method of simulating the interaction between a device and the native anatomy.7 The simulations use the geometric and mechanical properties of both the device and patient anatomy to predict the deformation of the device and the potential for important procedural complications. The technology has been studied in a number of structural heart procedures, including TAVI, left atrial appendage occlusion and transcatheter mitral valve replacement.8–20 Patient-specific computer simulation of TAVI in BAV has been undertaken in a number of small studies, but the largest validation and prospective clinical experience has been performed using the FEops HEARTguide technology.11,12,21–25 An overview of patient-specific computer simulation of TAVI in BAV is presented in Figure 1.

Finite Element Analysis

The first step in patient-specific computer simulation is to create a finite element model of the aortic root (Figure 2 and Supplementary Material Video 1). Pre-procedural cardiac CT imaging is segmented with inclusion of the left ventricular outflow tract, aortic root and the ascending aorta.

Patient-specific Computer Simulation of Bicuspid Aortic Valve Figure 1: Patient-specific Computer Simulation of Transcatheter Aortic Valve Implantation in Bicuspid Aortic Valve A

manufacturer. Mechanical properties of the nickel titanium (Nitinol) frames are obtained through in vitro radial compression testing, with radial force recorded throughout the compression and unloading cycle. Pre-dilatation is simulated and then the finite element model of the THV is positioned within the aortic root model. Finite element analysis (FEA) is performed to simulate the interaction between the THV and the native anatomy.

Computational Fluid Dynamics D

A and B: Pre-procedural cardiac CT imaging (A) is used to create a finite element model (B) of the aortic root. C,D: Finite element analysis is performed to simulate the interaction between the transcatheter heart valve and the native anatomy. E: The blood domain is extracted and computational fluid dynamics is used to simulate paravalvular regurgitation. F: The force exerted by the transcatheter heart valve on the left bundle branch is measured and used to simulate conduction disturbance.

Figure 2: Finite Element Analysis A

An overview of the computational fluid dynamics (CFD) is presented in Figure 3. The blood domain is first extracted from the FEA output. A fixed pressure gradient of 32 mmHg is applied across the aortic root, a value that was derived using invasive measurement from 60 patients with tricuspid aortic valve.14 CFD is performed and paravalvular regurgitation is recorded in the left ventricular outflow tract. Importantly, the CFD simulations do not model for valvular regurgitation. The simulations are performed with the bioprosthetic leaflets aligned with the native leaflets, given that non-alignment of the bioprosthetic leaflets has been demonstrated to have minimal impact on the computer simulation output.16

Conduction Disturbance Modelling

Conduction disturbance modelling is presented in Figure 4. The inferior border of the membranous septum is located and then a region extending to 15 mm below the aortic annulus is identified. This anatomical region of interest is a surrogate for the His bundle and proximal left bundle branch.29 The force exerted by the THV on the native anatomy is extracted from the FEA modelling. The percentage of the region of interest that is subject to pressure (contact pressure index) is recorded. Importantly, the simulations do not account for differences in THV frame rotation, given that this has been demonstrated to have minimal impact on the computer simulation output.13

Validation of Computer Simulations I

A–C: Pre-procedural cardiac CT imaging is used to create a finite element model of the aortic root. D,E: The aortic wall, leaflets and calcium are given different mechanical characteristics. F–L: Finite element analysis is performed to simulate the interaction between the transcatheter heart valve and the native anatomy.

The aortic root tissues, leaflets and calcification are modelled with different elastic material properties.13,26 These material characteristics were derived through a process of iterative back-calculation from 39 tricuspid aortic valve patients who had pre- and post-procedural cardiac CT.15 Aortic leaflet modelling has been developed for both Sievers type 0 and type 1 BAV.27 Furthermore, modelling can be performed to reflect both tricommissural, bicommissural raphe-type and bicommissural non-raphetype leaflet morphology.28 Finite element models have been developed for a number of THVs, including SAPIEN XT (Edwards Lifesciences), CoreValve, Evolut R, Evolut PRO, Evolut PRO+ (Medtronic), Lotus and ACURATE neo (Boston Scientific). The frame morphology is derived from micro-CT, or based on information shared by the device manufacturer. The strut width is obtained from optical microscopy, or again, based on information shared by the

Retrospective validation of the computer simulations has been performed in 37 patients who had pre- and post-procedural cardiac CT imaging, with further validation performed on seven patients who had peri-procedural transoesophageal imaging.9,12 The majority of these patients had Sievers type 1 BAV (82%). The FEA simulations were found to be reliable at predicting the THV frame deformation within the bicuspid anatomy. Validation of the CFD analysis has demonstrated that the simulations are reliable at predicting the development of moderate paravalvular regurgitation. A predicted paravalvular regurgitation of 13.6 ml/s was found to be 92% sensitive and 72% specific for predicting the development of moderate paravalvular regurgitation, representing a positive predictive value of 61% and a negative predictive value of 95%. Limited validation of the conduction disturbance modelling has been performed in 20 patients. A contact pressure index of 0.14 was found to have a sensitivity of 67% and a specificity of 72% for predicting the development of major conduction abnormalities (new left bundle branch block, Mobitz type II second-degree atrioventricular block or third-degree atrioventricular block), representing a positive predictive value of 100% and a negative predictive value of 50%.

Optimising Transcatheter Heart Valve Sizing and Positioning

The computer simulations may be used to optimise THV sizing and positioning to reduce the severity of predicted paravalvular regurgitation

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Patient-specific Computer Simulation of Bicuspid Aortic Valve Figure 3: Computational Fluid Dynamics Simulation A

1 mm*

3 m/s*

0 mm

0 m/s

A: Finite element analysis is performed to simulate the interaction between the transcatheter heart valve and the native anatomy. B: Areas of poor apposition are noted. C: The blood domain is extracted and then computational fluid dynamics is used to simulate paravalvular regurgitation. In this example, significant paravalvular regurgitation is predicted. D: Postoperative transthoracic echocardiography demonstrates mild–moderate paravalvular regurgitation. *Values above this maximum are displayed in the highest colour in the scale.

Figure 4: Conduction Disturbance Modelling A

0.4 MPa*

0.0 MPa

A: A patient with no conduction disturbance underwent transcatheter aortic valve implantation with a 29 mm Evolut R valve. B: Finite element analysis demonstrates elliptical frame deformation within the bicuspid valve. C: Conduction disturbance modelling suggests significant conduction disturbance. D: Following transcatheter aortic valve implantation, the patient developed complete heart block. *Values above this maximum are displayed in the highest colour in the scale.

and conduction disturbance (Figure 5).30 Simulations are performed using a THV sized using the perimeter-derived aortic annulus dimensions, and additional simulations may also be undertaken using a ‘downsized’ THV. Furthermore, simulations may also be performed with the THV positioned at multiple different implantation depths, typically at a high (0 mm), medium (4 mm), and, in some select cases, a deep (8 mm) implantation depth. Operators may then review the multiple simulations to choose the optimal THV size and implantation depth that reduces predicted paravalvular regurgitation and conduction disturbance.

Prospective Experience

To date, the clinical outcomes of 19 patients who have been treated prospectively using the technology have been presented.11,25 A significant number of these patients had tricommissural leaflet morphology (47%), but patients with bicommissural raphe-type (37%) and bicommissural nonraphe-type (16%) leaflet morphology were also studied (Table 1). The computer simulations have been demonstrated to be a useful aid for guiding treatment decisions in BAV patients. In particular, the CFD analysis may be used to identify patients whose aortic root anatomy may not be suitable for TAVI because of the potential to develop significant paravalvular regurgitation. In prospective clinical usage, the computer simulations have suggested that five patients might develop significant paravalvular regurgitation if treated with a self-expanding THV, and, following discussion in the heart team meeting, four of these patients were treated with surgery. One patient was thought by the heart team to have a too high risk for surgery and was treated with a balloon-expandable THV.

For the 14 patients who were treated with TAVI using a self-expanding THV, the computer simulations were found to be a useful guide for THV sizing and positioning, and in 10 of these patients, procedural aspects were altered to minimise paravalvular regurgitation. In one of these patients, a deep implant was predicted to minimise paravalvular regurgitation and therefore a pre-procedural permanent pacemaker was implanted, given that the computer simulations predicted significant conduction disturbance with a deep implantation depth. Favourable clinical outcomes have been observed in all 19 patients, with no patient developing moderate paravalvular regurgitation and no patient requiring post-procedural implantation of a permanent pacemaker.

Limitations

It is important that clinicians recognise the limitations of computer modelling. The FEA is not performed in a pressurised state and so is currently unable to simulate important procedural complications such as THV embolisation. Furthermore, the aortic root tissues are modelled with elastic material properties and therefore the FEA is unable to simulate aortic root rupture. The correct modelling of aortic leaflet morphology is dependent on high-quality cardiac CT imaging studies. Only limited validation of the FEA has been performed for patients with Sievers type 0 (bicommissural non-raphe-type) BAV. The CFD simulations do not have perfect diagnostic accuracy. Conduction disturbance modelling may not be feasible in all patients, given that adequate

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Patient-specific Computer Simulation of Bicuspid Aortic Valve Figure 5: Patient-specific Transcatheter Heart Valve Sizing and Positioning A

3 m/s*

0 m/s

0.4 MPa*

0.0 MPa

Finite element analysis simulations have been performed with a 29 mm Evolut PRO (A,B) and 34 mm Evolut R (C,D) transcatheter heart valve implanted at high (A,C) and at medium (B,D) implantation depths. The computational fluid dynamics simulations (E–H) and conduction disturbance modelling (I–L) suggest that predicted paravalvular regurgitation and conduction disturbance will be lowest with a 29 mm Evolut PRO transcatheter heart valve positioned at a high implantation depth. *Values above this maximum are displayed in the highest colour in the scale.

Table 1: Baseline Characteristics of Prospectively Treated Patients Characteristic

n=19

Age (years)

78.9 ± 8.1

Male

13 (68.4)

EuroSCORE II (%)

7.0 ± 6.2

Mean aortic valve gradient (mmHg)

48.6 ± 18.1

Aortic valve morphology Sievers classification Sievers type 0

3 (15.8)

Sievers type 1

16 (84.2)

TAVR-directed BAVi morphological classification Tricommissural

9 (47.4)

Bicommissural raphe type

7 (36.8)

Bicommissural non-raphe type

3 (15.8)

BAVi = bicuspid aortic valve imaging; TAVR = transcatheter aortic valve replacement.

right‑sided contrast opacification is required. Although multiple computer simulations may be performed to model a variety of different THV positions, achieving a target implantation depth may not always be feasible with current-generation self-expanding devices, because of the risk of device migration or embolisation on release.31 Furthermore, repositioning of the THV may induce trauma to the conduction tissue, although this risk might be mitigated by the top-down deployment technique, which is being evaluated in the Optimize PRO study (NCT04091048). The FEops HEARTguide technology is currently unable to model the SAPIEN 3 THV (Edwards Lifesciences), which has been associated with favourable procedural outcomes in bicuspid anatomy, although patient-specific computer simulation of BAV with this THV has been performed by other groups.22,32 Due to time and financial constraints, use of the technology may not be feasible in all patients, and its usage could potentially be limited to patients with high-risk complex anatomical subsets, such as patients with a calcified raphe or excess leaflet calcification, or for patients with a tapered aortic root anatomy, for whom THV downsizing might be considered.33,34

Future Directions

It is important to consider how patient-specific computer simulation of BAV could best be implemented into routine clinical practice. Ideally,

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Patient-specific Computer Simulation of Bicuspid Aortic Valve technologies such as deep learning would be used to rapidly identify patients with BAV at the time of cardiac CT acquisition.35 Cardiac CT imaging might then be transferred onto a cloud-based platform, where deep learning algorithms could assist with automatic segmentation of aortic root structures, reducing case processing times.36,37 Computer simulation output could then be provided to treating physicians in an expedited manner.38 To date, limited prospective experience exists with patient-specific computer simulation of TAVI in BAV. To address this shortcoming, the PRECISE TAVI study (NCT04473443) will examine the role of patientspecific computer simulation in heart team decision-making in complex anatomy. Optimal THV device selection for bicuspid anatomy is yet to be established and patient-specific computer simulation could potentially be used to guide the selection of a high-radial-force or high-conformity THV.21 Ultimately, there exists the potential for patient-specific THVs to be developed, which would be tailored to the patient’s precise anatomical characteristics and could potentially reduce both paravalvular regurgitation and conduction disturbance.26 Finally, further studies will be needed to determine if hospital outcomes of TAVI in BAV patients might benefit from other uses of artificial intelligence, 1. Dowling C, Kondapally Seshasai SR, Firoozi S, Brecker SJ. Transcatheter aortic valve replacement versus surgery for symptomatic severe aortic stenosis: a reconstructed individual patient data meta-analysis. Catheter Cardiovasc Interv 2020;96:158–66. https://doi.org/10.1002/ccd.28504; PMID: 31566902. 2. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation 2005;111:920–5. https://doi.org/10.1161/01. cir.0000155623.48408.c5; PMID: 15710758. 3. Yoon SH, Bleiziffer S, De Backer O, et al. Outcomes in transcatheter aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. J Am Coll Cardiol 2017;69:2579–89. https://doi.org/10.1016/j.jacc.2017.03.017; PMID: 28330793. 4. Halim SA, Edwards FH, Dai D, et al. Outcomes of transcatheter aortic valve replacement in patients with bicuspid aortic valve disease: a report from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Circulation 2020;141:1071–9. https://doi.org/10.1161/ circulationaha.119.040333; PMID: 32098500. 5. Pibarot P, Hahn RT, Weissman NJ, et al. Association of paravalvular regurgitation with 1-year outcomes after transcatheter aortic valve replacement with the SAPIEN 3 valve. JAMA Cardiol 2017;2:1208–16. https://doi.org/10.1001/ jamacardio.2017.3425; PMID: 28973091. 6. Jørgensen TH, De Backer O, Gerds TA, et al. Mortality and heart failure hospitalization in patients with conduction abnormalities after transcatheter aortic valve replacement. JACC Cardiovasc Interv 2019;12:52–61. https://doi.org/10.1016/j. jcin.2018.10.053; PMID: 30621978. 7. El Faquir N, Ren B, Van Mieghem NM, et al. Patient-specific computer modelling: its role in the planning of transcatheter aortic valve implantation. Neth Heart J 2017;25:100–5. https://doi.org/10.1007/s12471-016-0923-6; PMID: 27888494. 8. Brouwer J, Nijenhuis VJ, Gheorghe L, et al. The accuracy of patient-specific computer modelling in predicting device size and paravalvular aortic regurgitation in complex transcatheter aortic valve replacement procedures. Structural Heart 2020;4:320–8. https://doi.org/10.1080/24748706.2020. 1765442. 9. Brouwer J, Gheorghe L, Nijenhuis VJ, et al. Insight on patient specific computer modeling of transcatheter aortic valve implantation in patients with bicuspid aortic valve disease. Catheter Cardiovasc Interv 2019;93:1097–105. https:// doi.org/10.1002/ccd.27990; PMID: 30461187. 10. El Faquir N, De Backer O, Bosmans J, et al. Patient-specific

such as deep learning, which has been demonstrated to be predictive of short-term outcomes in other fields of cardiovascular diseases, such as carotid artery stenting.39

Conclusion

As the use of TAVI continues to expand into the younger, lower-risk patient cohort, achieving excellent clinical outcomes in BAV is important. Patientspecific computer simulation is an emerging technology that may be used by the heart team to guide the transcatheter treatment of patients with BAV.

Clinical Perspectives

• Patient-specific computer simulation of transcatheter aortic valve

implantation in bicuspid aortic valve may predict the development of important clinical outcomes such as paravalvular regurgitation and conduction disturbance • Patient-specific computer simulation may be used to optimise transcatheter heart valve sizing and positioning to minimise predicted paravalvular regurgitation and conduction disturbance • The usage of patient-specific computer simulation to risk-stratify bicuspid patients and to optimise transcatheter heart valve sizing and positioning has been associated with favourable clinical outcomes

computer simulation in TAVR with the self-expanding Evolut R valve. JACC Cardiovasc Interv 2020;13:1803–12. https://doi.org/10.1016/j.jcin.2020.04.018; PMID: 32682679. 11. Dowling C, Firoozi S, Brecker SJ. First-in-human experience with patient-specific computer simulation of TAVR in bicuspid aortic valve morphology. JACC Cardiovasc Interv 2020;13:184–92. https://doi.org/10.1016/j.jcin.2019.07.032; PMID: 31629752. 12. Dowling C, Bavo AM, El Faquir N, et al. Patient-specific computer simulation of transcatheter aortic valve replacement in bicuspid aortic valve morphology. Circ Cardiovasc Imaging 2019;12:e009178. https://doi.org/10.1161/ circimaging.119.009178; PMID: 31594409. 13. Rocatello G, El Faquir N, De Santis G, et al. Patient-specific computer simulation to elucidate the role of contact pressure in the development of new conduction abnormalities after catheter-based implantation of a selfexpanding aortic valve. Circ Cardiovasc Interv 2018;11:e005344. https://doi.org/10.1161/ circinterventions.117.005344; PMID: 29386188. 14. de Jaegere P, De Santis G, Rodriguez-Olivares R, et al. Patient-specific computer modeling to predict aortic regurgitation after transcatheter aortic valve replacement. JACC Cardiovasc Interv 2016;9:508–12. https://doi. org/10.1016/j.jcin.2016.01.003; PMID: 26965945. 15. Schultz C, Rodriguez-Olivares R, Bosmans J, et al. Patientspecific image-based computer simulation for the prediction of valve morphology and calcium displacement after TAVI with the Medtronic CoreValve and the Edwards SAPIEN valve. EuroIntervention 2016;11:1044–52. https://doi. org/10.4244/eijv11i9a212; PMID: 26788707. 16. Collas VM, Rocatello G, El Faquir N, et al. Effect of commissural alignment on paravalvular aortic regurgitation after TAVI. Journal of Heart Valve Disease 2018–19;28:1–7. 17. Bavo AM, Wilkins BT, Garot P, et al. Validation of a computational model aiming to optimize preprocedural planning in percutaneous left atrial appendage closure. J Cardiovasc Comput Tomogr 2020;14:149–54. https://doi. org/10.1016/j.jcct.2019.08.010; PMID: 31445885. 18. de Jaegere P, Rajani R, Prendergast B, et al. Patient-specific computer modeling for the planning of transcatheter mitral valve replacement. J Am Coll Cardiol 2018;72:956–8. https:// doi.org/10.1016/j.jacc.2018.05.064; PMID: 30115237. 19. Allen CJ, Patterson T, Prendergast B, et al. Simultaneous transcatheter double valve treatment of mediastinal radiation-induced severe calcific aortic and mitral stenosis. JACC Case Rep 2020;2:1443–7. https://doi.org/doi:10.1016/j. jaccas.2020.07.003. 20. Karády J, Ntalas I, Prendergast B, et al. Transcatheter mitral valve replacement in mitral annulus calcification: “the art of

computer simulation”. J Cardiovasc Comput Tomogr 2018;12:153–7. https://doi.org/10.1016/j.jcct.2017.12.007; PMID: 29325812. 21. Finotello A, Romarowski RM, Gorla R, et al. Performance of high conformability vs. high radial force devices in the virtual treatment of TAVI patients with bicuspid aortic valve. Med Eng Phys 2021;89:42–50. https://doi.org/10.1016/j. medengphy.2021.02.004; PMID: 33608124. 22. Pasta S, Cannata S, Gentile G, et al. Simulation study of transcatheter heart valve implantation in patients with stenotic bicuspid aortic valve. Med Biol Eng Comput 2020;58:815–29. https://doi.org/10.1007/s11517-020-02138-4; PMID: 32026185. 23. Lavon K, Marom G, Bianchi M, et al. Biomechanical modeling of transcatheter aortic valve replacement in a stenotic bicuspid aortic valve: deployments and paravalvular leakage. Med Biol Eng Comput 2019;57:2129–43. https://doi. org/10.1007/s11517-019-02012-y; PMID: 31372826. 24. Gorla R, Casenghi M, Finotello A, et al. Outcome of transcatheter aortic valve replacement in bicuspid aortic valve stenosis with new-generation devices. Interact Cardiovasc Thorac Surg 2021;32:20–8. https://doi.org/10.1093/ icvts/ivaa231; PMID: 33201993. 25. Dowling C, Gooley R, McCormick L, et al. TCT CONNECT-121 Ongoing experience with patient-specific computer simulation of transcatheter aortic valve replacement in bicuspid aortic valve. J Am Coll Cardiol 2020;76(17 Suppl):B53. https://doi.org/doi:10.1016/j.jacc.2020.09.135. 26. Rocatello G, De Santis G, De Bock S, et al. Optimization of a transcatheter heart valve frame using patient-specific computer simulation. Cardiovasc Eng Technol 2019;10:456– 68. https://doi.org/10.1007/s13239-019-00420-7; PMID: 31197702. 27. Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg 2007;133:1226–33. https://doi.org/10.1016/j. jtcvs.2007.01.039; PMID: 17467434. 28. Jilaihawi H, Chen M, Webb J, et al. A bicuspid aortic valve imaging classification for the TAVR era. JACC Cardiovasc Imaging 2016;9:1145–58. https://doi.org/10.1016/j. jcmg.2015.12.022; PMID: 27372022. 29. Kawashima T, Sasaki H. A macroscopic anatomical investigation of atrioventricular bundle locational variation relative to the membranous part of the ventricular septum in elderly human hearts. Surg Radiol Anat 2005;27:206–13. https://doi.org/10.1007/s00276-004-0302-7; PMID: 15723154. 30. Dowling C, Bavo A, Mortier P, et al. TCT-414 Patient-specific computer simulation to optimise transcatheter heart valve sizing and positioning in bicuspid aortic valve morphology. J Am Coll Cardiol 2018;72(13 Suppl):B167. https://doi.org/

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Patient-specific Computer Simulation of Bicuspid Aortic Valve doi:10.1016/j.jacc.2018.08.1576. 31. Kim WK, Schäfer U, Tchetche D, et al. Incidence and outcome of peri-procedural transcatheter heart valve embolization and migration: the TRAVEL registry (TranscatheteR HeArt Valve EmboLization and Migration). Eur Heart J 2019;40:3156–65. https://doi.org/10.1093/eurheartj/ ehz429; PMID: 31230081. 32. Makkar RR, Yoon SH, Leon MB, et al. Association between transcatheter aortic valve replacement for bicuspid vs tricuspid aortic stenosis and mortality or stroke. JAMA 2019;321:2193–202. https://doi.org/10.1001/jama.2019.7108; PMID: 31184741. 33. Yoon SH, Kim WK, Dhoble A, et al. Bicuspid aortic valve morphology and outcomes after transcatheter aortic valve replacement. J Am Coll Cardiol 2020;76:1018–30.

https://doi.org/10.1016/j.jacc.2020.07.005; PMID: 32854836. 34. Tchetche D, de Biase C, van Gils L, et al. Bicuspid aortic valve anatomy and relationship with devices: the BAVARD Multicenter Registry. Circ Cardiovasc Interv 2019;12:e007107. https://doi.org/10.1161/circinterventions.118.007107; PMID: 30626202. 35. Dowling C, Astudillo P, Brecker S, et al. Classification of aortic valve morphology using a three-dimensional convolutional neural network. Presented at: PCR London Valves 2019, 17–19 November 2019, London, UK. 36. Astudillo P, Mortier P, Bosmans J, et al. Enabling automated device size selection for transcatheter aortic valve implantation. J Interv Cardiol 2019;2019:3591314. https://doi. org/10.1155/2019/3591314; PMID: 31777469. 37. Astudillo P, Mortier P, Bosmans J, et al. Automatic detection

of the aortic annular plane and coronary ostia from multidetector computed tomography. J Interv Cardiol 2020;2020:9843275. https://doi.org/10.1155/2020/9843275; PMID: 32549802. 38. Ribeiro JM, Astudillo P, de Backer O, et al. Artificial intelligence and transcatheter interventions for structural heart disease: a glance at the (near) future. Trends Cardiovasc Med 2021. https://doi.org/10.1016/j. tcm.2021.02.002; PMID: 33581255; epub ahead of press. 39. Amritphale A, Chatterjee R, Chatterjee S, et al. Predictors of 30-day unplanned readmission after carotid artery stenting using artificial intelligence. Adv Ther 2021;38:2954–72. https://doi.org/10.1007/s12325-021-01709-7; PMID: 33834355.

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Coronary

Factors Influencing Stent Failure in Chronic Total Occlusion Coronary Intervention Kalaivani Mahadevan ,1 Claudia Cosgrove

and Julian W Strange1

1. Department of Cardiology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK; 2. Department of Cardiology, St George’s University NHS Trust, London, UK

Abstract

Stent failure remains one of the greatest challenges for interventional cardiologists. Despite the evolution to superior second- and third-generation drug-eluting stent designs, increasing use of intracoronary imaging and the adoption of more potent antiplatelet regimens, registries continue to demonstrate a prevalence of stent failure or target lesion revascularisation of 15–20%. Predisposition to stent failure is consistent across both chronic total occlusion (CTO) and non-CTO populations and includes patient-, lesion- and procedure-related factors. However, histological and pathophysiological properties specific to CTOs, alongside complex strategies to treat these lesions, may potentially render percutaneous coronary interventions in this cohort more vulnerable to failure. Prevention requires recognition and mitigation of the precipitants of stent failure, optimisation of interventional techniques, including image-guided precision percutaneous coronary intervention, and aggressive modification of a patient’s cardiovascular risk factors. Management of stent failure in the CTO population is technically challenging and itself begets recurrence. We aim to provide a comprehensive review of factors influencing stent failure in the CTO population and strategies to attenuate these.

Keywords

Stent failure, in-stent restenosis, stent thrombosis, chronic total occlusion, stenting strategy Disclosure: The authors have no conflicts of interest to declare. Received: 14 January 2021 Accepted: 7 June 2021 Citation: Interventional Cardiology 2021;16:e27. DOI: https://doi.org/10.15420/icr.2021.03 Correspondence: Julian W Strange, Bristol Heart Institute, 68 Horfield Rd, Bristol BS2 8ED, UK. E: julian.strange@uhbw.nhs.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Stent failure (SF) is a widely used term enveloping the aetiologies of in-stent restenosis (ISR), stent thrombosis (ST) and stent fracture (StF). The mechanisms of each vary: ISR is most commonly secondary to neointimal hyperplasia or neoatherosclerosis; ST is often precipitated by malapposition and incomplete stent strut coverage; and StF, although much rarer, is caused most frequently by vessel motion at hinge points. In addition to these factors, a number of patient comorbidities, as well as coronary lesion characteristics, procedural strategies and stent design factors, increase the risk of SF. Despite the evolution of stent platforms and increasing adoption of precision percutaneous coronary intervention (PCI) facilitated by adjunctive calcium modification and the use of intracoronary imaging, SF poses an ongoing challenge to coronary revascularisation. Although the shift from bare-metal stents (BMS) to drugeluting stents (DES) saw a decrement in overall ISR rates, ISR remains the primary culprit for failure of contemporary PCI.1 Target lesion revascularisation (TLR) rates of between 3% and 20% are consistently reported across randomised controlled trials (RCTs) and large registries, regardless of the coronary vessel treated, lesion complexity or the use of image-guided stent optimisation.2–5 In both the EXCEL and NOBLE trials, with >70% uptake of intravascular ultrasound (IVUS) for left mainstem PCI and the use of DES, TLR rates of approximately 12% were reported.6,7 Similar trends have been seen in trials of coronary artery bypass grafting (CABG) versus PCI incorporating complex multivessel coronary disease and diabetic cohorts, proven to be at increased SF risk, with TLR rates of 19% in the SYNTAX trial at the 5-year follow-up, 5.7% in the BEST trial and 12.6% in the FREEDOM trial.8–10

ISR and TLR are also common phenomena following PCI for chronic total occlusion (CTO), a challenging subset of coronary disease, the treatment of which frequently induces greater vessel trauma. In the ACE-CTO study of 100 patients following implantation of second-generation everolimuseluting stents (EES), the 12-month TLR rate was 37%.11 However, significantly lower TLR and target vessel revascularisation (TVR) rates have been shown in both RCTs and registries. For example, an evaluation of long-term clinical outcomes following CTO PCI in three tertiary centres found TLR and ST rates of 17.2% and 1.7%, respectively, with use of DES.12 More recently, the CONSISTENT CTO study found TVR rates of 4.8% and 17% in non-diabetic and diabetic cohorts, respectively.13 Although earlier data, such as those from the J-Cypher 5-year outcomes study, demonstrated higher rates of TLR in CTO PCI versus unselected non-CTO PCI, more recent data directly comparing outcomes of CTO PCI versus complex non-CTO PCI found equipoise in target vessel failure (TVF) at the 3-year follow-up.14,15 This was despite higher cardiovascular comorbidity, a lower degree of procedural success and higher complication rates in the CTO treated cohort. The aim of this review is to provide a structured and comprehensive summary of the primary factors influencing and predicting SF (Figure 1), primarily ISR, in the CTO population, alongside strategies to mitigate these.

Patient-related Factors

Numerous comorbidities and clinical entities increase the absolute risk of SF secondary to ISR and ST. In this review, we focus on diabetes, chronic kidney disease (CKD) and dyslipidaemia.

Factors Influencing Stent Failure in CTO PCI Figure 1: Classification of Factors Affecting Stent Failure in Percutaneous Coronary Intervention for Chronic Total Occlusion Patient-related factors: Diabetes CKD Dyslipidaemia Hypertension Platelet hyper-reactivity Prothrombotic state DAPT compliance Increased bleeding risk

Procedure-related factors: Hybrid strategy Use of IVUS Stent platform No. stents deployed Underexpansion Malapposition Final MLD/MSA Edge dissection TIMI Grade 3 flow

Stent failure in CTO PCI Lesion-related factors: Increasing lesion length Small vessel diameter Negative remodelling Calcific disease Increasing J-CTO score Aorto-ostial/bifurcation cap Lesion in grafted vessel In-stent CTO

Pharmacotherapy/lifestyle factors: Antiplatelet regime Smoking Exercise Dietary optimisation Risk factor control Compliance Early reporting of symptom recurrence

CKD = chronic kidney disease; CTO = chronic total occlusion; DAPT = dual antiplatelet therapy; IVUS = intravascular ultrasound; MLD = minimum lumen diameter; MSA = minimum stent area; PCI = percutaneous coronary intervention; TIMI = thrombolysis in MI.

Diabetes

Diabetes is prevalent in approximately 40% of patients undergoing CTO PCI and is an independent predictor of ISR.16 Intimal hyperplasia is promoted by vessel trauma during stenting, and the effects of hyperinsulinaemia on smooth muscle cells, leading to luminal loss, reduced minimal luminal area and subsequent TLR/TVR.17 A 980-patient single-centre observational study comparing outcomes in diabetics with HbA1c <7% versus >7% showed increased major adverse cardiovascular events (MACE), driven primarily by repeat revascularisation, in those with poorer glycaemic control (TLR and non-TLR).18 These findings are echoed in other large studies and a meta-analysis demonstrating trends towards increased ISR and TLR in diabetic cohorts with a higher HbA1c or glucose level at index PCI, with increasing severity of disease predicting increased TLR in a stepwise manner.19,20 Furthermore, one large study showed TVR rates to be significantly increased in diabetic patients with poor glycaemic control compared with non-diabetic patients, whereas in diabetic subjects with good glycaemic control the outcomes were equivalent to those in a non-diabetic matched population, reinforcing the importance of vigilant glycaemic management.21 Similar findings were observed in the CONSISTENT CTO study, in which TVR rates were significantly higher at both 12 months (15.9% versus 4.8%) and 2 years (27.3% versus 7.8%) in diabetic versus non-diabetic cohorts undergoing CTO PCI.13

Chronic Kidney Disease

Almost 30% of patients undergoing CTO PCI have Stage III CKD, defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, either as an end-organ manifestation of diabetes or hypertension or secondary to alternative renal or systemic pathology.22 CKD is associated with accelerated and aggressive atherosclerotic coronary disease, increased MACE (including post-coronary revascularisation) and higher SF rates. Mechanisms linked to conventional coronary risk factors include activation of the renin–angiotensin–aldosterone system in hypertensive patients, increased insulin-like growth factor in diabetic patients and malignant patterns of dyslipidaemia, including upregulation of LDL receptor expression and increased triglyceridaemia. Furthermore, higher levels of novel coronary risk factors, including homocysteine and certain

forms of apolipoprotein, have been consistently found in CKD patients alongside increased oxidative stress and reductions in endothelial nitric oxide levels (crucial for vascular integrity).23 Trials in coronary intervention frequently exclude CKD patients, 80% excluding end-stage renal disease and 60% excluding any CKD, due to the challenges of revascularisation in these patients resulting from increased coronary calcification and the need to minimise contrast load.24 In a pooled analysis of over 12,000 patients in the Korean Multi-Center DES registry, TLF was significantly higher in the CKD versus preserved renal function cohort, with a trend towards increased ST at 30 days.25 In the Japanese Multicentre Prospective Registry outcomes analysis of 4,749 patients, an eGFR <30 ml/min/1.73 m2 and haemodialysis dependence were associated with reduced procedural success (primarily due to failure of retrograde wire cross), higher in-stent occlusion rates (p<0.001), increased lesion calcification, proximal tortuosity and occlusion length >20 mm, and subsequently higher J-CTO scores.26 Further, dialysis dependence was a predictor of 12-month major adverse cardiovascular and cerebrovascular events driven by death, TVR and CABG.26 An eGFR <40 ml/min/1.73 m2, alongside diabetes, left ventricular (LV) ejection fraction <45%, volumedeplete hypotension, increasing age and anaemia, predicts an increased risk of contrast-induced nephropathy (CIN).27 Irreversible deterioration in eGFR secondary to CIN, leading to progressive CKD, is associated with increased longer-term MACE, mediated through accelerated atherosclerosis, vascular calcification and effects on LV remodelling.27 European Society of Cardiology recommendations advocate renal optimisation through transient withholding of nephrotoxic medications, intravenous pre- and post-hydration, limited contrast use (lowest of either <350 ml or <4 ml/kg) and serum creatinine monitoring post procedure.28 LV end-diastolic pressure-guided fluid replacement in the POSEIDON study and the use of the RenalGuard (RenalGuard Solutions) system in the REMEDIAL II study both demonstrated a reduced risk of CIN compared with matched control cohorts.29,30 These strategies should be appropriately adopted to optimise both short- and longerterm renal outcomes, preventing irreversible progression of CKD, which itself begets SF. Further, with the advent of precision IVUS-guided PCI, the ability to safely perform complex intervention with minimal or zero contrast use has been demonstrated and is being incorporated into clinical practice.31

Dyslipidaemia

Dyslipidaemia is highly prevalent in the CTO population, at over 70% in the European Registry of CTO, and frequently coexists with diabetes and CKD.32 LDL, the target of statin therapy in preventive cardiovascular pharmacotherapeutics, has long been known as a risk factor for coronary artery disease.33 More recently, VLDL was found to be an independent predictor of ISR in people with diabetes after DES implantation.33 This was hypothesised to be mediated via the pathophysiological effects of apolipoproteins (Apo) B and C.34,35 However, HDL and ApoA1, the socalled ‘good cholesterol’, have been linked in vitro to improved stent biocompatibility through inhibition of smooth muscle cell proliferation, the suppression of inflammation and the prevention of neointimal hyperplasia.36 Furthermore, ApoA1 promotes re-endothelialisation following vessel trauma and stent implantation via generation of nitric oxide and facilitation of endothelial repair.36 This process is fundamental to stent strut coverage and hence prevention of ST. The REVEAL trial was the first to show an association between anacetrapib (a cholesterol ester transfer protein

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Factors Influencing Stent Failure in CTO PCI Figure 2: Considerations and Longer-term Effects for Stent Sizing Pathological considerations for stent sizing Late (acquired) malapposition

Small calibre distal vessel due to chronic hypoperfusion

Stent thrombosis

Late luminal growth

Stent oversizing

Medial disruption

Neointimal growth

In-stent restenosis

Source: Spratt et al.43 Reproduced with permission from Optima Education.

inhibitor)-driven increases in HDL and ApoA1 levels and a reduction in atherosclerotic vascular events, including cardiac death, MI and coronary revascularisation.37 Hence, rigorous management of cholesterol components, through lowering of LDL and VLDL while increasing HDL, appears important in halting aggressive atherosclerotic processes and optimising physiological stent biocompatibility.

Lesion-related Factors

Lesion length, location, composition and complexity are predictors of SF. Increasing CTO length predicts escalation through the hybrid algorithm and subsequent procedural success. In a retrospective analysis by Tian et al., 5-year outcomes demonstrated CTO length >15 mm to be a predictor of TLR, whereas Ahn et al. found CTO length >30 mm was associated with higher repeat PCI driven by TVR at 2 years.38,39 In the diabetic cohort of the OPEN-CTO study, approximately 60% had occlusion length >20 mm, whereas in the dissection and re-entry technique (DART) cohort of the CONSISTENT-CTO study, a mean (± SD) lesion length of 32 ± 22 mm was associated with an overall 2-year TVR of 14.9%, reiterating the potential for ISR and, further, development of downstream in-stent CTO.13,40 CTO location at the aorto-ostium or bifurcation increases procedural difficulty and carries a higher risk of SF. Aorto-ostial lesions are independent predictors of quantitative coronary angiography-based longitudinal stent deformation (LSD), and carry a higher chance of geographical miss, potentially leaving behind a nidus for TVR/TLR.41 The presence of a major bifurcation (within the proximal cap, occluded segment or distal cap) has been reported in 26–47% of CTO lesions and is associated with increased procedural complexity and longer-term MACE (primarily driven by reduced side-branch Thrombolysis in Myocardial Infarction [TIMI] flow and periprocedural MI).42 The strongest predictor of technical success where there is within-CTO side-branch involvement, is luminal side branch wiring at baseline, mitigating side branch loss, although this is not always feasible.42

Lesion composition is dependent on CTO duration. Younger lesions display features of organised thrombus and necrotic core. Older lesions contain greater quantities of fibrous tissue and calcium, with a higher prevalence of negative remodelling.43 Heavily calcified lesions, particularly during the use of a subintimal (SI) strategy when aggressive modification carries an increased risk of perforation, are vulnerable to stent underexpansion or restriction, leading to an increased risk of both ISR and ST.43 Longerduration CTO lesions without calcium often demonstrate significant negative remodelling, increasing the risk of vessel rupture with 1 : 1 stent sizing and leading to smaller minimum stent area (MSA), another independent predictor of ISR.43 Pathological considerations for stent sizing are shown in Figure 2. Post-CABG, CTO PCI adds an additional dimension of complexity to CTO recanalisation. Up to 40% of venous bypass grafts and 15% of internal mammary artery grafts occlude within 10 years.44 A study of native vessel patency after CABG demonstrated at least one new CTO in 43.6%.45 PreCABG native vessel stenosis >90% and Canadian Cardiovascular Society Class IV angina at baseline were independent predictors of subsequent postoperative CTO formation.45 Post-bypass CTO lesions exhibit increased calcification, negative remodelling and blunt proximal cap (Figure 3), rendering wire escalation strategies less successful (38%) than in nonCABG CTO (57%) and requiring early adoption of retrograde or DART strategies.46,47 Although TVR and MACE were higher in the post-CABG cohort, reassuringly 85% of patients remained event free at 1 year despite the complexity of their disease and procedural technique, alongside increased comorbidity.47 The in-stent (IS) CTO cohort poses further treatment complexity. Specific challenges include luminal wiring of previously under-expanded stents, with a higher likelihood of SI entry at the proximal cap (Figure 4) and increased calcification in these often longer-duration occlusions. Initial experiences of IS-CTO revascularisation reported success rates of 71%, whereas operator up-skilling and the use of novel devices have led to

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Factors Influencing Stent Failure in CTO PCI Figure 3: Accelerated Development of Proximal Native Vessel Disease Post-Coronary Artery Bypass Grafting on CT Coronary Angiography Calcification of SVG

Vein graft RMB

PRC Calcification of RCA MRC DRC

Potential factors predisposing to proximal disease progression and more complex CTO formation post-CABG: • High burden of atherosclerosis pre-CABG. • Low flow and reduced shear stress. • Increased calcification, tortuosity and lesion length • Accelerated atherosclerosis proximal to graft • Increased incidence of blunt distal cap in post-bypass CTOs

CABG = coronary artery bypass grafting; CTO = chronic total occlusion; DRC = distal right coronary artery; MRC = middle right coronary artery; PD = posterior descending artery; PRC = proximal right coronary artery; RCA = right coronary artery; RMB = right marginal branch; SVG = saphenous vein graft. Source: Spratt et al.43 Reproduced with permission from Optima Education.

Figure 4: Challenge of Luminal Wiring With In-stent Chronic Total Occlusion

Increased risk of wire entry to the stented segment behind the struts rather than within the struts. Angulation (demonstrated) and stent under expansion (not demonstrated) will increase this risk further

associated long-term TLR/TVR. An analysis of predictors of re-occlusion after DES supported CTO PCI in 802 successfully revascularised patients from the Florence CTO Registry, reporting a re-occlusion rate of 7.5%.53 The use of an SI tracking and re-entry (STAR) technique was associated with the highest re-occlusion rate (57%), compared with 5.1% in the non-STAR cohort.53 This was echoed in the J-PROCTOR 2 Study, where increased TVR was noted in a retrograde SI tracking cohort, and in a small meta-analysis of five studies where DART was associated with increased longer-term adverse events.54,55 However, the DART strategy itself is important, with use of newer device-based (CrossBoss and Stingray, Boston Scientific) approaches demonstrating significantly lower rates of MACE compared with older wire-based (STAR, limited antegrade subintimal tracking and controlled antegrade and retrograde tracking and dissection) techniques (8.9% versus 22.1%, respectively).56 Further, in regression analyses, wire-based DART and stent length were independent predictors of MACE.56,57 The use of DART in an earlier study by Rinfret et al. had a minimal impact on longer-term outcomes after CTO PCI and, most recently, SI stenting (48.1% of the cohort) in the CONSISTENT-CTO study neither adversely affected intravascular healing at 12 months nor was associated with higher TVR at 2 years.13,58 Differences between study outcomes, particularly those seen in CONSISTENT-CTO, may be explained by the higher rates (91%) of TIMI grade 3-defined procedural success and the adoption of pre-stenting IVUS (90.5% of cases).13 The results of the LOTUS ADR/RDR study, assessing long-term outcomes, including binary restenosis at the 13-month angiographic follow-up, 2-year TVR and validation of a dedicated restenosis score (R-Score) of related risk factors, are awaited.59

Intravascular Ultrasound

Proximal cap begins before stented segment

Source: Spratt et al.43 Reproduced with permission from Optima Education.

significant improvements, with an 86% success rate reported in both the PROGRESS-CTO registry and another large study by Azzalini et al.48,49 This is comparable to that of de novo CTO PCI, recognised to be around 90% when performed in high-volume centres by experienced CTO operators.13,48 Nevertheless, IS-CTO PCI carries a predilection to increased TLR and is independently associated with both increased MACE and repeat revascularisation.50 The prediction of CTO lesion complexity and procedural success through dedicated scoring systems is well established. Of these systems, the most commonly used J-CTO score has more recently been associated with trends in predicting 5-year TLR.51 In post-CABG CTO cohorts, the RECHARGE score (which includes a weighting for CABG) was deemed superior to the J-CTO score as an independent predictor of longer-term adverse outcomes, including TVF.52

Procedure-related Factors Chronic Total Occlusion Recanalisation Strategy

Results of studies of the hybrid algorithm components (antegrade wire escalation, antegrade dissection and re-entry, retrograde wire escalation and retrograde dissection and re-entry) are mixed with regard to strategy-

The use of IVUS in all PCIs has increased over the past decade. Global uptake and operator beliefs around the benefits of IVUS are highly variable by region.60 Although the British Cardiovascular Interventional Society’s national audit data show overall uptake at approximately 12%, a large study by Mentias et al. of more than 1 million Medicare patients in the US demonstrated an increase in IVUS use of only 3.9% (from 3% to 6.9%) between 2009 and 2017.61,62 However, another multicentre US registry reported a 38% frequency of IVUS.63 Hence, data are varied, perhaps (in the US) influenced to some extent by reimbursement. In contrast, in Japan, the country with the highest use of IVUS, registry data report >80% uptake.64 IVUS serves numerous roles, including: resolution of proximal cap ambiguity and guidance of cap penetration; facilitation of antegrade and retrograde DART techniques and prevention of dissection into the aorta; vessel and stent sizing; identification of appropriate landing zones, negative remodelling and calcium; and optimisation of stent expansion and apposition. IVUS also appropriately identifies nodular calcium and the extent to which the SI channel is in the adventitial space. This allows prediction of the risk of perforation with over-zealous post-dilatation, guiding the operator to accept a degree of eccentric stent expansion when appropriate and reasonable. The use of IVUS is associated with improved long-term outcomes in CTO PCI. Although the AVIO trial of angiography versus IVUS-guided PCI of complex lesions showed no significant difference in 2-year MACE, TLR or TVR, subgroup analysis revealed improved minimum lumen diameter (MLD) in the IVUS arm.65 However, CTO-specific analysis of IVUS versus angiography in the Korean-CTO registry found reductions in MACE, ST and TLR in longer (>30 mm) lesions in the AIR-CTO Study showed significantly lower rates of late lumen loss and ‘in-true-lumen’ stent restenosis and the CTO-IVUS Trial demonstrated reduction in MACE at 12 months.66–68 Hence, the use of IVUS, both up-front and for stent optimisation, can be deemed crucial in the prevention of longer-term

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Factors Influencing Stent Failure in CTO PCI SF and should be routinely used, regardless of CTO lesion complexity or recanalisation strategy. Importantly, the demonstrated benefits of IVUS are reliant upon accurate image acquisition, interpretation and management of findings. RCTs of IVUS are prescriptive, protocolised to optimise results and often involve operators with greatest expertise, producing optimal outcomes. This is not reflective of real-world practice. Further, the importance of a final IVUS can be exemplified using rates of longitudinal stent deformation (LSD). In registry data, mean rates of approximately 1.2% are reported.41 However, the EXCEL substudy of stent deformation observed a 6.5% prevalence of LSD.69 This reiterates the importance of a final imaging run to systematically detect and correct anomalies predicting downstream SF such as LSD, tissue prolapse and edge dissection, in addition to ensuring good stent apposition and expansion.

Stenting Strategy

Stenting strategy, determined by stent platform, diameter, total stent length and post-deployment optimisation, is a key determinant of downstream SF. Evolution from BMS to DES witnessed significant reductions in ISR. This was mediated through reduced neointimal hyperplasia owing to DES bioactivity and reduced ST due to non-endothelialised stent struts, due, in part, to suppression of local inflammatory responses. A meta-analysis of 26,000 patients across 20 studies again supports the superiority of DES, with Picollo et al. demonstrating ST rates at 1- and 5-year follow-up after DES and BMS implantation of 0.6%, 1.1%, 8.4% and 13.4%, respectively, and corresponding TLR rates of 4% and 8.8%, 8.4% and 13.4%, respectively (p<0.001 for all).70 CTO-specific analysis of DES platforms in the FLORENCE-CTO Registry demonstrated superiority of EES over other DES, with significantly lower re-occlusion rates (3% versus 10.1%).53 However, other studies have found no significant differences between use of first- and second-generation DES, including Moreno et al., who demonstrated equipoise for restenosis between EES and sirolimuseluting stent (SES) platforms following CTO PCI.71–73 Stent design, including strut thickness, radial strength and longitudinal integrity, affects the risk of LSD, StF and stent usability. Thinner strut designs that allow increased deliverability, trackability and vessel conformability are particularly advantageous in CTOs with tortuous and calcific anatomy or where coronary reconstruction with a ‘metal jacket’ of overlapping stents is required. Early studies of BMS, comparing thick (140 µm) and thin (50 µm) stent struts, found significant differences in both angiographic restenosis and TVR in favour of the thin strut design.74,75 This is supported by a recent network meta-analysis of 69 randomised controlled trials including over 80,000 patients, which demonstrated reductions in ST and MI with the use of ultrathin versus thick strut DES.76 The switch from stainless steel to cobalt chromium alloy in these thinner strut platforms allowed preservation of radial strength. However, clinical experience and data show a trade-off in longitudinal strength, rendering thinner strut designs more vulnerable to LSD.77 Although infrequent, with rates of 1.2% reported in the literature, LSD precipitates ST, TLF and MACE.41 Mechanisms relating to LSD are multifactorial, including, in addition to strut thickness, the number of connectors and their orientation. In bench testing, Ormiston et al. demonstrated that stent platforms with two connectors between hoops had reduced longitudinal strength on exposure to external forces compared with designs with six connectors, concluding that fewer connectors directly compromises longitudinal integrity.78 For example, the Promus Premier platform (Boston Scientific), a newer iteration of the two-

connector Promus Element platform, saw the addition of extra connectors at the proximal stent end while maintaining a two-connector design through the main stent body, mitigating the occurrence of LSD while maintaining deliverability.79 This is an important consideration, particularly in the undertaking of aorto-ostial and bifurcation PCI. StF, as a precipitant of SF, has been reported to occur at rates of 1–3% and is isolated to DES.80 Kuramitsu et al. studied StF of EES, finding increased MACE driven by ST and TLR (25.6% versus 2.3% in the nonStF group; p<0.001).80 Ostial stent location and lesions with hinge motion, tortuosity or increased calcium (prevalent in native and post-CABG CTOs) were independent predictors of StF.81 Platforms with increased radial strength serve to reduce the risk of StF in such lesions. In contrast to LSD, an increase in connectors confers greater risk of StF due to rigidity and reduced conformability to vessel anatomy and motion.79 An additional consideration in CTO PCI is the risk of stent undersizing due to negative remodelling, subintimal haematoma or poorer flow. Choosing a platform that can be appropriately overexpanded, particularly in long lesions or where there is distal and proximal vessel size mismatch, is important. This feature of the stent is primarily based on crown and connector design. The data demonstrate that with increasing overexpansion, crown straightening occurs.82 Although this can increase radial strength, it reduces flexibility and conformity, predisposing to StF. In addition, increased stent cell opening diameter can lead to intrastrut plaque prolapse and impair uniform drug elution, again risking SF.82 Balancing these factors when making stent choices during CTO PCI is key in longerterm procedural outcomes, and on-going development of the optimal stent platform continues as newer iterations manifest. Stent length, akin to lesion length, alongside the number of stents deployed, predicts ISR. Ahn et al. studied outcomes after DES in long (>30 mm) versus short (<30 mm) CTO lesions.83 Although no significant differences in binary restenosis, late lumen loss or MLD were seen at the 6-month angiographic follow-up, higher repeat PCI driven by TVR was noted at 2 years.83 In the Korean CTO registry, lesion length >20 mm (p<0.01) and the use of at least three DES (p<0.001) were associated with MACE, TVR and TLR at a median follow-up of 22 months.84 Stent diameter and subsequent MSA are also strong predictors of SF. The combined TAXUS IV, V, VI and ATLAS Workhorse Trials’ IVUS substudy analysis of 1,580 patients demonstrated post-IVUS MSA >5.7 mm2 predicted 9-month angiographic stent patency.85 In smaller vessels, postintervention optical coherence tomographyassessed MSA <3.5 mm2 was found to be a predictor of 9-month ISR and TLR following PCI with a 2.5-mm diameter EES.86 IVUS analysis of MSA across different stent platforms (zotarolimus-eluting stent, EES and SES), revealed similar optimal MSA cut-off values for predicting ISR (5.2 mm2 and 5.4 mm2), with a smaller MSA predictive of angiographic ISR in firstand second-generation DES.87 In a CTO-specific study, Kang et al. found that the MLD and stent expansion ratio were independent predictors of ISR.88 These findings support the importance of image-guided PCI in CTO lesions to: allow accurate estimates of vessel sizing (and therefore stent diameter choice), particularly in the presence of vessel dissection or haematoma; rationalise maximal stent length; identify and appropriately modify calcium to facilitate stent expansion; and optimise stent expansion through post-dilation to achieve greatest MLD, MSA and stent expansion ratio in prevention of downstream ISR and ST.

Pharmacological Factors

Increased vessel trauma, the length of the stented segment and postrevascularisation vessel remodelling, alongside the often highly comorbid nature of this patient group, render the CTO PCI cohort at high risk for SF.

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Factors Influencing Stent Failure in CTO PCI RCT evidence over the past decade has led to paradigm shifts in dual antiplatelet regimes, with ticagrelor the preferred addition to aspirin for acute coronary syndrome presentations.89 In PCI for stable angina, Clopidogrel has remained the second agent of choice in addition to aspirin. Few studies specifically assess optimal platelet reactivity/responsivity or dual antiplatelet therapy choice after CTO PCI. The first analysis of platelet reactivity in a CTO cohort emerged from the FLORENCE CTO registry of more than 1,000 patients who underwent platelet function testing by light transmission aggregometry.90 The high platelet reactivity cohort had significantly increased cardiac mortality at 3 years compared with an optimal platelet reactivity cohort (p<0.001). Further, when those with high platelet reactivity were identified and clopidogrel (standard of care) switched to either prasugrel or ticagrelor, the survival rates seen were similar to those in the optimal platelet reactivity group.90 The TIGER trial, although small, demonstrated that ticagrelor pretreatment (compared with clopidogrel) improved downstream coronary vascular flow following CTO recanalisation, with the longer-term potential to improve ischaemia and reduce TLR.91 This is supported by data identifying TIMI flow grade as an independent predictor of TVF.92 Although larger RCTs to identify the optimal dual antiplatelet therapy strategy following CTO PCI are required and current guidelines offer no consensus, decisions will be at operator 1. Bonaa K, Mannsverk J, Wiseth R, et al. Drug eluting or bare metal stents for coronary artery disease. N Engl J Med 2016;375:1242–52. https://doi.org/10.1056/NEJMoa1607991; PMID: 27572953. 2. Stolker JM, Cohen DJ, Kennedy KF, et al. Repeat revascularisation after contemporary percutaneous coronary intervention; an evaluation of staged, target lesion and other unplanned revascularization procedures during the first year. Circ Cardiovasc Interv 2012;5:772–82. https://doi. org/10.1161/CIRCINTERVENTIONS.111.967802; PMID: 23093553. 3. Kandzari DE, Leon MB, Meredith I, et al. Final 5-year outcomes from the Endeavor zotarolimus-eluting stent clinical trial program: comparison of safety and efficacy with first-generation drug-eluting and bare-metal stents. JACC Cardiovasc Interv 2013;6:504–12. https://doi.org/10.1016/j. jcin.2012.12.125; PMID: 23602459. 4. Sarno G, Lagerqvist B, Fröbert O, et al. Lower risk of stent thrombosis and restenosis with unrestricted use of ‘newgeneration’ drug-eluting stents: a report from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Eur Heart J 2012;33:606–13. https://doi. org/10.1093/eurheartj/ehr479; PMID: 22232428. 5. Navarese EP, Kowalewski M, Kandzari D, et al. Firstgeneration versus second-generation drug-eluting stents in current clinical practise: updated evidence from a comprehensive meta-analysis of randomised clinical trials comparing 31 379 patients. Open Heart 2014;1:e000064. https://doi.org/10.1136/openhrt-2014-000064; PMID: 25332803. 6. Stone GW, Kappetein AP, Sabik JF, et al. Five-year outcomes after PCI or CABG for left main coronary disease. N Engl J Med 2019;381:1820–30. https://doi.org/10.1056/ NEJMoa1909406; PMID: 31562798. 7. Makikallio T, Holm N, Lindsey M, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective randomised, open label, non-inferiority trial. Lancet 2016;388:2743–52. https://doi.org/10.1016/S01406736(16)32052-9; PMID: 27810312. 8. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery by-pass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381:629–38. https://doi. org/10.1016/S0140-6736(13)60141-5; PMID: 23439102. 9. Park SJ, Ahn JM, Kim YH, et al. Trial of everolimus-eluting stents or bypass surgery for coronary disease. N Engl J Med 2015;372:1204–12. https://doi.org/10.1056/NEJMoa1415447; PMID: 25774645. 10. Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularisation in patients with diabetes. N Engl J Med 2012;367:2375–84. https://doi.org/10.1056/ NEJMoa1211585; PMID: 23121323. 11. Kotsia A, Navara R, Michael TT, et al. The AngiographiC Evaluation of the Everolimus Eluting Stent in Chronic Total

discretion and should factor in comprehensive assessment of patientspecific ischaemic and bleeding risk, alongside the complexity of CTO recanalisation, the extent of vessel stenting and final TIMI flow grade.

Conclusion

SF in both non-CTO and CTO PCI is multifactorial, involving patient comorbidities, cardiovascular risk factor control, lesion complexity, stenting strategy and, finally, antiplatelet and adjunctive medical therapy. As the prevalence of ischaemic risk factors continues to rise, preventive and therapeutic measures to mitigate these are paramount in the reduction of longer-term MACE and repeat revascularisation. Advances in interventional techniques, the development of novel devices and operator upskilling have led to the undertaking of PCI in increasingly complex and high-risk patient subsets. Specific to CTO PCI, increased calcification, the challenges of lesion preparation and stent optimisation in the SI space, where perforation risk is higher, and the potential for stent undersizing at the index procedure is greater, due to negative remodelling and haematoma increase the risk of SF. Therefore, it is crucial to optimise outcomes using a multipronged approach via aggressive medical therapy, lifestyle modification and meticulous image-guided precision PCI to reduce SF in these challenging patient cohorts.

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Structural

Pre-dilation and Post-dilation in Transcatheter Aortic Valve Replacement: Indications, Benefits and Risks Angela McInerney , Rafael Vera-Urquiza, Gabriela Tirado-Conte , Luis Marroquin , Pilar Jimenez-Quevedo, Iván Nuñez-Gil, Eduardo Pozo, Nieves Gonzalo , Jose Alberto de Agustín, Javier Escaned, Antonio Fernández-Ortiz, Carlos Macaya and Luis Nombela-Franco Cardiovascular Institute, Hospital Clínico San Carlos, IdISSC, Madrid, Spain

Abstract

Transcatheter aortic valve replacement (TAVR) is an established treatment for patients with symptomatic severe aortic stenosis. In recent years, an emphasis has been placed on simplification of the procedure. Balloon predilation was initially considered a mandatory step to cross and prepare the stenotic aortic valve, but several studies demonstrated the feasibility of performing TAVR without balloon valvuloplasty. Balloon postdilation of the implanted valve is sometimes required to optimise results, although many patients do not require this step. Contemporary consensus advocates an individualised approach to TAVR procedures and so balloon pre- and post-dilation are performed selectively. This review aims to outline the advantages and disadvantages of balloon pre- and post-dilation and to identify the scenarios in which they are required during TAVR procedures.

Keywords

Transcatheter aortic valve implantation, transcatheter aortic valve replacement, predilation, postdilation, stroke, paravalvular leak Disclosure: LNF has served as a proctor for Abbott and received speaker honoraria from Edwards Lifesciences. All other authors have no conflicts of interest to declare. Received: 30 December 2020 Accepted: 17 June 2021 Citation: Interventional Cardiology 2021;16:e28. DOI: https://doi.org/10.15420/icr.2020.35 Correspondence: Luis Nombela-Franco, Instituto Cardiovascular, Hospital Universitario Clínico San Carlos, IdISSC, c/ Prof Martin Lagos s/n, 28040 Madrid, Spain. E: luisnombela@yahoo.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In the 10 years since the original randomised controlled clinical trials were published examining the role of transcatheter aortic valve replacement (TAVR) in the treatment of severe symptomatic aortic stenosis, TAVR devices have evolved and the choice of TAVR devices has grown at an exponential rate. The TAVR procedure has also evolved, with an emphasis on simplified procedures that involve less frequent balloon valvuloplasty (BAV) of the native valve, less rapid pacing with less frequent need for transvenous temporary pacing wires, and increasing use of the radial approach for non-therapeutic access. BAV, once considered a mandatory step, is now reserved for specific circumstances, as is postdilation of TAVR prostheses. As such, an individualised approach to the TAVR procedure is required. Given the continually growing use of, and knowledge about, TAVR and its extension to low-risk patients, it seems appropriate to revisit the evidence available on BAV and balloon postdilation (BPD). Therefore, the aims of this review are to consider the current data and to identify in which patients and situations their use should be recommended.

Pre-dilation

BAV was initially considered a mandatory step when performing TAVR. The first randomised controlled trials demonstrating the efficacy of TAVR versus conservative management included BAV as part of the implantation technique and treatment of the control group.1 The mechanical effects of BAV (fracturing of the calcium and separation of fused cusps) increase the orifice area to theoretically allow smoother passage of

the TAVR prosthesis through the stenosed valve, prepare the valve for TAVR implantation, and ensure uniform expansion of the prosthesis by decreasing radial counterforces, thereby avoiding paravalvular leak (PVL) or valve malposition. In particular, self-expanding TAVR valves often have a lower radial force and may be underexpanded when deployed without predilation, especially in severely calcified aortic valves. Successive iterations of TAVR devices have, however, come some way in resolving these potential issues, and direct TAVR implantation is now more frequently used. Lower profile delivery systems allow smoother passage of the prosthesis across the stenosed valve, and stronger radial force with better expansion of the valve within the annulus as well as improved understanding of aortic valve assessment using 3D echocardiography or CT imaging has led many operators to consider BAV no longer mandatory. Operator experience also plays a role, with a trend towards decreased BAV use in more experienced centres.2 A number of registries and meta-analyses have suggested that preBAV could perhaps be omitted. In 2011, Grube et al. published the first series of 60 patients who had been prospectively enrolled and who had undergone direct CoreValve implantation, and compared them with a retrospective cohort of patients who had undergone pre-BAV.3 Procedural technical success, as defined by the first Valve Academic Research Consortium (VARC) criteria, was 96.7%, with BPD being required in 16.7%.4 Thereafter, a number of registries, matched studies and meta-analyses demonstrated similar device success in patients undergoing BAV

Balloon Pre-dilation and Post-dilation in TAVR versus direct TAVR in studies with balloon-expandable prostheses, selfexpandable prostheses, and in studies containing both types.2,5–14 The result has been a progressive decline in the use of BAV before TAVR, with many registries demonstrating direct TAVR implantation in approximately 50% of patients.2,15

Nonetheless, greater troponin rises have been noted with predilation and rapid pacing, suggesting that the haemodynamic effects of these steps can result in myocardial damage, which should be considered, particularly in patients who have baseline ventricular dysfunction.12,23

Given, however, that many of the studies included in these meta-analyses were registries without randomisation or prespecified criteria for preBAV versus direct TAVR, it is inevitable that there exists a selection bias in terms of those patients who underwent BAV versus those who had direct TAVR. It was therefore not until recently, with the publication of the DIRECT and DIRECTAVI trials, that randomised controlled trial data on this issue became available (Table 1).16,17

The close relationship between the aortic valve annulus and the atrioventricular conduction system explains the potential risk of conduction disorders during and after TAVR implantation.24 The His bundle penetrates the membranous septum, the superior border of which lies at, or just superior to, the aortic annulus. The inferior border of the membranous septum marks the transition from the penetrating to the branching segments of the His bundle.24 Mechanical damage and resulting oedema and compression to the atrioventricular conduction system can result in transient or permanent conduction disorders after TAVR. Post-TAVR conduction abnormalities have been associated with poorer outcomes in terms of both rehospitalisation and increased mortality.25

The DIRECT trial was a multicentre, open-labelled randomised controlled trial of 171 patients randomised either to pre-BAV (86 patients) or to direct TAVR implant (85 patients) with the self-expanding CoreValve system (mostly Evolut R generation, Medtronic). Device success, as defined by the VARC-2 criteria, was found to be similar in both groups, with direct implantation being non-inferior to implantation after BAV (76.5% in the pre-BAV group versus 74.4% in the direct implant group; mean difference, 2.1%; 90% CI [−8.9%, 13%]).16,18 Similarly, the DIRECTAVI trial was a single-centre randomised controlled trial randomising patients to pre-BAV versus direct TAVR with a balloonexpandable prosthesis (Edwards Sapien 3, Edwards Lifesciences).17 Again, device success was similar, and non-inferior for direct implantation versus pre-BAV (80.2% for direct implantation versus 75.7% for pre-BAV; mean difference, 4.5%; 95% CI [−4.4%, 13.4%]; p=0.02 for non-inferiority). It should be noted that crossover to pre-BAV was required in 5.8% of the patients (43% of cases were due to failure to cross the valve, and 57% were based on complex anatomy such as bicuspid valve, low aortic valve area [AVA] and high valve calcium score).17 Other studies have found additional benefits to the omission of pre-BAV including simplification of the TAVR procedure, resulting in reduced procedure time, reduced contrast volume, fewer cases of acute kidney injury (AKI) and reduced fluoroscopy time; these findings, however, were not replicated in the DIRECTAVI trial.5,6,12,17,19,20 As such, pre-BAV is likely to remain an important step for some patients, and understanding the potential risks and benefits is essential when choosing the TAVR strategy for an individual patient (Figure 1). These will be discussed in the following sections.

Potential Risks of Predilation Haemodynamic Instability

Haemodynamic instability is often cited as an associated risk of BAV. BAV is performed under rapid pacing, which can result in haemodynamic instability, as can the often severe aortic insufficiency that occurs due to separation of the aortic commissures. Prior to the widespread use of TAVR, BAV as a treatment for aortic stenosis resulted in severe aortic regurgitation in 1–2% of patients.21 Furthermore, the EASE-IT TA registry of patients with trans-apical TAVR using the Sapien 3 valve found a lower requirement for catecholamine use in patients who had direct TAVR implantation, suggesting a more balanced haemodynamic state (catecholamine use, 17.5% in the direct TAVR group versus 32.8% in the BAV group, p=0.017).22 However, the same finding was not replicated in the EASE-IT TF registry and, furthermore, in an analysis of the Brazilian TAVR registry, Bernardi et al. reported haemodynamic instability related to valve positioning in those patients undergoing direct TAVR implantation in 2.8% of cases.6,14

Conduction Disorders

Omission of pre-BAV was thought to reduce the permanent pacemaker (PPM) rate. In fact, in the EASE-IT TF registry the perceived risk of atrioventricular block was cited as the reason for avoiding pre-BAV in 22% of cases planned for implantation of the Edwards Sapien 3 valve.6 Nuis et al. have previously shown that 46% of new conduction disorders occurring during implantation of the CoreValve system occurred after BAV, with a high proportion persisting at discharge; and similarly, an analysis of the Brazilian TAVR registry demonstrated higher rates of new-onset left bundle branch block (LBBB) that persisted at discharge in patients who received a CoreValve after pre-BAV.14,26 A ‘two-hit model’ was proposed by Lange et al., in which the conduction system received a first hit during BAV (resulting in inflammation and intramural haematoma), with the second hit being valve implantation.27 In that study, smaller balloon sizes used for BAV were associated with a lower PPM requirement, a so-called ‘moderate’ predilation approach (PPM rate, 27.1% after predilation with a 25 mm balloon versus 15.4% for a 23 mm balloon, p=0.04), in keeping with the findings by Nuis et al. of higher rates of conduction abnormalities with higher balloon:annulus ratios.26,27 Additionally, Grube et al. in their initial study noted a lower PPM rate in the group with direct TAVR implantation compared with the historic group of patients with BAV (11.7% versus 27.8%, respectively).3 In contrast, some meta-analysis and registry studies have reported either decreased PPM rates or a neutral effect of BAV on pacemaker rates.5,10,11,13 Furthermore, neither DIRECTAVI nor the DIRECT trial had increased PPM rates in their pre-BAV arms (Table 1).16,17 Although not proven in randomised studies to increase PPM risk, it is wise to consider other known contributing factors such as valve choice, and pre-existing conduction disorders before deciding on the final procedural plan and whether this should include pre-BAV or not.28,29

Acute Kidney Injury

Theoretically, hypotension caused by rapid pacing, increased procedural time and increased contrast use in cases of balloon sizing can contribute to kidney injury. A meta-analysis of 18 studies by Liao et al. demonstrated reduced contrast requirement (by ~20 ml) with a tendency to reduced AKI (p=0.08) in patients who had direct TAVR implantation compared with those who had pre-BAV.10 Other studies have also found a reduced requirement for contrast use: the SOURCE 3 registry reported less contrast use in the direct TAVR group by 4.8 ml, which did not translate into differences in AKI (1.4% versus 0.5%, p=0.069 for direct TAVR versus pre-BAV, respectively), while a study by Bijuklic et al. also found that the

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Balloon Pre-dilation and Post-dilation in TAVR Table 1: Summary of the Design and Outcomes of the DIRECT and DIRECTAVI Trials Trial

Devices used

Study design and no. of participants

Outcome

Results

DIRECT 201916

CoreValve (11.7%) Evolut R (83.6%) Evolut Pro (4.7%)

Study design Multicentre open-label RCT

Primary endpoint Device success defined by VARC-2 criteria

Primary endpoint • Direct implant 29.4% Device success • Pre-BAV 15.1% • Pre-BAV group 76.5% p=0.03 • Direct TAVR 74.4% Mean difference 2.1%; 90% CI [−8.9%, 13%]

DIRECTAVI 202017 Edwards Sapien 3 (100%)

Participants n=171 • 86 pre-BAV • 85 direct TAVR

Study design Prospective, single-centre, open-labelled RCT Participants n=236 • 115 pre-BAV • 121 direct TAVR

Secondary endpoint In-hospital or 30 day • Stroke • New permanent pacemaker • Vascular complications

Primary endpoint Device success at 72 h defined by VARC-2 criteria Secondary endpoints

• Length of procedure • Radiation exposure • Contrast volume • Hospitalisation length • All-cause mortality • Stroke • Major bleeding • AKI stage 2–3 • Pacemaker implantation

Postdilation rate

Secondary endpoints Stroke (p=0.32) • Pre-BAV group 0% • Direct TAVR 0.01% New permanent pacemaker (p=0.54) • Pre-BAV group 27.5% • Direct TAVR 32.8% Major vascular complications (p=0.49) • Pre-BAV group 5.8% • Direct TAVR 3.5%

Primary endpoint Device success (p=0.02 for non-inferiority) • Pre-BAV group 75.7% • Direct TAVR 80.2% Mean difference 4.5%; 95% CI [−4.4%, 13.4%]

• Direct implant 1.7% • Pre-BAV 1.7% p=1.00

Secondary endpoints Length of procedure (p=0.31) • Pre-BAV group 54.2 ± 18.2 min • Direct TAVR 52.0 ± 18.7 min Radiation exposure (p=0.24) • Pre-BAV group 3,730 ± 3,487 cGy/cm2 • Direct TAVR 4,073 ± 3,293 cGy/cm2 Contrast volume (p=0.97) • Pre-BAV group 78.2 ± 29.3 ml • Direct TAVR 79.7 ± 33.3 ml Hospitalisation length (p=0.90) • Pre-BAV group 5.3 ± 23.0 days • Direct TAVR 4.9 ± 2.2 days All-cause mortality (p=0.24) • Pre-BAV group 0% • Direct TAVR 3.2% Stroke (p=0.99) • Pre-BAV group 0.9% • Direct TAVR 1.7% Major bleeding (p=0.70) • Pre-BAV group 2.6% • Direct TAVR 4.1% AKI stage 2–3 (p=0.37) • Pre-BAV group 0.9% • Direct TAVR 3.3% Pacemaker implantation (p=0.72) • Pre-BAV group 20.9% • Direct TAVR 19.01%

AKI = acute kidney injury; BAV = balloon valvuloplasty; RCT, randomised controlled trial; TAVR = transcatheter aortic valve replacement; VARC = Valve Academic Research Consortium.

direct TAVR group had a reduced contrast use by ~17 ml.5,30 However, the randomised DIRECTAVI trial using a balloon-expandable valve did not find a difference in contrast volume used or in AKI between the direct implantation and predilation groups.17 Nor were there differences in AKI between groups in the DIRECT trial.16 In unrandomised trials, predilation with increased contrast use during the procedure may be

more reflective of complex anatomy rather than a specific requirement for more contrast with predilation. Furthermore, balloon sizing may be performed with a contrast injection while the balloon is inflated to assess for aortic regurgitation and aid in choosing the prosthesis size. However, this practice is now much less commonly used now that CT imaging is routinely performed. In our institution, balloon sizing is rarely used, and

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Balloon Pre-dilation and Post-dilation in TAVR Figure 1: Advantages and Disadvantages of Balloon Pre- and Post-dilation in Transcatheter Aortic Valve Replacement

• Uniform prosthesis expansion • Reduced PVL • Reduced need for BPD

• Reduce PVL • Optimise TAVR frame expansion • Optimise valve gradients

Predilation

Postdilation

• Haemodynamic instability • Longer procedure time • Requirement for rapid pacing • Acute kidney injury • Conduction disorders

• Valve embolisation • Conduction disorders • Valve leaflet damage • Stroke • Annular rupture

BPD = balloon postdilation; PVL = paravalvular leak; TAVR = transcatheter aortic valve replacement.

in cases in which predilation is performed, additional contrast injections are not used.

Stroke

Cerebral embolisation of debris during TAVR implantation has been a concern since the first TAVR valves were implanted. The rate of 30-day postprocedure stroke ranges between 2% and 4% in large registries and trials.31–33 Excessive manipulation of the native valve during TAVR is thought to contribute to the periprocedural stroke risk, and this is supported by studies using cerebral protection devices in which cardiac tissue including from valve leaflets, aorta and myocardium has been found on histological assessment of captured debris.34 However, in the aforementioned study by Van Mieghem et al., pre-TAVR BAV was not associated with increased debris in the cerebral protection device.34 Furthermore, other singlecentre and registry studies have not shown an association between preBAV and stroke at 30 days, and nor have the recent DIRECTAVI and DIRECT randomised controlled trials (predilation versus direct TAVR, 0.9% versus 1.7%, p=0.99 in the DIRECTAVI trial and 0% versus 0.01% in the DIRECT trial).6,17,32 Transcranial Doppler studies identifying cerebral embolisation during TAVR suggest that device positioning and BPD of TAVR valves may be a more important predictor of cerebral embolisation of particulate matter.35,36 Also, BPD has been associated with higher rates of clinically evident cerebrovascular events.33,37 Thus, avoiding predilation to reduce the potential risk of cerebral embolisation during BAV may not be justified if the BPD rate increases in a direct TAVR approach, which has been seen in a number of studies including the DIRECT trial.11,16,20

Paravalvular Leak and Requirement for Postdilation

Conflicting evidence exists regarding the incidence of PVL in patients with and without pre-BAV. Some have hypothesised that direct implantation avoids disruption of the valvular calcium and allows the valve to sit more securely, thereby avoiding PVL, while others suggest that preparation of the calcium avoids non-circular valve expansion and underexpansion, along with the resulting residual PVL and higher valve gradients, which

may be a particular issue with self-expanding valves. Although some studies have found a higher need for postdilation in direct implantation patients, others have found a less frequent need or no difference in postdilation frequency with direct TAVR.5,6,8,11,20 The DIRECTAVI trial using a balloon-expandable valve did not demonstrate any difference in rates of postdilation between those who had predilation versus those who did not.17 However, the converse was true in the DIRECT trial, again using the CoreValve system, in which postdilation was required more frequently in the direct implant arm (29.4% versus 15.1%, p=0.03).16 Neither study, however, demonstrated differences in aortic regurgitation at discharge between the groups, suggesting that postdilation can adequately resolve the issue of PVL.

General Recommendations on Predilation

Although randomised data exist regarding the outcomes of direct TAVR versus predilation, recommendations for the specific clinical or anatomical scenarios in which predilation should be performed, are lacking. However, given that no consensus exists, this section will therefore detail the approach at our centre to performing predilation. The accompanying algorithm may provide some guidance to identify those patients in whom predilation is required and those who may be suitable for direct TAVR implantation (Figure 2). Our practice has been to consider three fundamental aspects: the clinical assessment of the patient, anatomical considerations, and the planned valve choice.

Clinical Assessment

Patients with impaired left or right ventricular systolic function may have a poorer tolerance of the haemodynamic shifts caused by rapid pacing during BAV. Our practice therefore has been to avoid predilation in patients vulnerable to the effects of hypotension such as those with reduced right or left ventricular function, severe chronic kidney disease, and those who may already be haemodynamically compromised, such as those undergoing rescue TAVR procedures. Additionally, patients who are unlikely to tolerate prolonged procedures or prolonged periods of

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Balloon Pre-dilation and Post-dilation in TAVR Figure 2: Decision Algorithm for Predilation in Transcatheter Aortic Valve Replacement Other reasons to consider BAV • Valve sizing • Assessment of coronary occlusion

Patient planned for TAVR

High-risk patients • Low LVEF (<30%) • Reduced right ventricular function • Pre-existing haemodynamic instability • Other reasons to avoid rapid pacing • Severe chronic kidney injury • Short procedure desirable Yes

Yes

Unfavourable anatomy • AVA <0.4cm2 • Severe valve calcification • Bulky calcium nodules • Bicuspid valve • Horizontal aorta >48° • Aortic tortuosity

Yes

Valve choice

BEV

SEV

Recapturable

Consider direct TAVR

Non-recapturable

Consider BAV

AVA = aortic valve area; BAV = balloon valvuloplasty; BEV = balloon-expandable valve; LVEF = left ventricular ejection fraction; SEV = self-expanding valve; TAVR = transcatheter aortic valve replacement.

sedation or intubation (severe pre-existing lung disease) are considered in our institution for direct TAVR implantation.

Anatomical Considerations

At our institution, multi-slice CT for valve sizing, access site choice and assessment of aortic tortuosity or angulation is performed for all patients, as is a thorough transthoracic echocardiogram. In this manner a thorough, anatomical assessment is performed to identify patients who will require pre-BAV. Islas et al. identified a number of echocardiography criteria that highlight patients for whom direct TAVR is unfavourable, including AVA <0.4 cm2, irregular valve orifice, presence of calcium nodules, and leaflet calcification greater than grade 2.19 Other studies have also reported on anatomical characteristics (Agatston calcium score and lower AVA) that have been associated with difficulties in crossing the stenosed valve.17,38,39 Predilation is therefore considered in heavily calcified valves (Agatston score >5,000) with severe stenosis at our institution. Excessive tortuosity or angulation of the aorta may lead to difficulties in crossing the native valve with the prosthesis. In self-expanding valves an aortic root angulation of >48° has been found to result in reduced device success with increased PVL. Excessive aortic root angulation may therefore be another consideration in the decision to perform BAV before TAVR.40 Congenital or acquired abnormalities of aortic valve morphology are also an important consideration. Bicuspid (either functional or ‘true’ type 0) aortic valve disease remains a complex anatomical subset, and studies on TAVR in these patients have used predilation in almost 100% of cases, which, until TAVR for bicuspid aortic valve disease comes into more widespread use, is likely to remain the recommended approach, and is our preferred approach.38,39 Balloon migration and asymmetrical elliptical stent frame expansion might be seen in patients with bicuspid valve and could be minimised with BAV. The 2017 American College of Cardiology

consensus document for the use of TAVR in the management of severe aortic stenosis has also suggested that predilation may be useful if the coronary ostia are low-lying to assess the risk of coronary obstruction with valve implantation.41 In our experience, however, we do not use BAV for this purpose and elect instead to protect the coronary ostia by wiring with or without a stent prepared for deployment, depending on the risk and valve type.

Prosthesis Choice

Our final consideration is the prosthesis we plan to use. Self-expanding prostheses are known to have lower radial force and may be underexpanded or obtain a more eccentric geometry after deployment.42 Although evidence exists that the CoreValve family may be implanted without the use of predilation, we have a lower threshold for performing pre-BAV with CoreValve compared with balloon-expandable valves. Cases of infolding of the valve prosthesis have been reported with the CoreValve system and are thought to be related to eccentric calcification of the aortic annulus.43–46 Although postdilation can be used to correct infolding, predilation may be a more effective way of preventing valve infolding. Other self-expanding systems such as the Portico (Abbott Vascular) and ACURATE Neo devices (Boston Scientific) are almost always deployed after predilation at our institution. However, the ability to recapture the Portico device allows more flexibility if the prosthesis is severely underexpanded during the deployment process, in contrast to the ACURATE neo valve, which cannot be recaptured once the deployment process has begun. We consider it therefore even more important to perform predilation when using non-recapturable self-expandable valves. Our recommendation is to use a predilation semi-compliant balloon diameter equal to the minimum diameter of the aortic annulus for recapturable self-expanding valves, and a diameter 1–2 mm larger than the minimum diameter for nonrecapturable self-expanding valves.

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Balloon Pre-dilation and Post-dilation in TAVR Figure 3: Rate of Balloon Postdilation in Current Studies with Different Transcatheter Aortic Valve Replacement Systems Mechanical expanding

Self-expanding 60

Balloon-expandable

BPD (%)

40 30 20 10 0 Barbanti

Harrison Manoharan Pagnesi CoreValve71 CoreValve53 Evolut R72 Evolut Pro74

Linke Søndergaard Pagnesi Portico75 Portico76 ACURATE neo74

Lanz Tamburino De Backer ACURATE ACURATE Lotus79 neo77 neo78

Feldman Lotus80

Hahn Sapien47

Mack Wendler Sapien 381 Sapien 382

Saia Sapien Ultra83

Rheude Sapien Ultra84

BPD = balloon postdilation; TAVR = transcatheter aortic valve replacement.

Postdilation

Optimal prosthesis frame expansion, reduction of PVL severity, improved effective orifice area and less patient–prosthesis mismatch have been noted after BPD of TAVR prostheses and are the main indications for BPD.47,48 In the OCEAN trial, the absence of balloon postdilation was associated with a 1.9-fold increased risk of patient–prosthesis mismatch on multivariable analysis.48 This is particularly important given that there is growing evidence that PPM may be a contributing factor to clinical and subclinical valve thrombosis.49 In the case of valve-in-valve TAVR, postdilation of the implanted valve with the aim of cracking the original surgical bioprosthesis and improving the effective orifice area of the TAVR, as well as improving the transvalvular gradients, has been recently adapted.50–52 However, paravalvular aortic regurgitation is the principal reason for performing BPD of TAVR valves.53 PVL occurs when there is incomplete apposition of the TAVR valve against the aortic wall.54 Avoidance of PVL remains one of the challenges of TAVR, given that the rate of PVL has been systematically higher following TAVR than with surgical aortic valve replacement in studies to date.55 However, newer devices have a much lower incidence of PVL, which is now commonly reported as being between 3% and 6%, and has clearly decreased over time.56–58 A number of predictors of PVL have been identified, including severe calcification of the aortic valve leaflets, large annulus dimensions, significant annular eccentricity, eccentricity index of the implanted prosthesis on CT, upper left ventricular outflow tract (LVOT) calcification, landing zone calcification, LVOT non-tubularity, aortic angulation >48° (in self-expandable devices), and lower device:annulus size ratio.37,40,42,53,59–65 Many of these risk factors can be identified on the pre-TAVR CT, and the appropriate prosthesis and prosthesis size to minimise PVL can be selected based on CT measurements, which has contributed to the decreasing rate of this complication and resulted in less frequent use of BPD.66,67 PVL, however, remains associated with poorer outcomes at followup, including mortality and readmissions, and therefore minimising PVL before the end of the procedure is important.68–72 Despite technological advances in TAVR prostheses, BPD remains a frequently performed adjunctive procedure even with newer generation valves (Figure 3).47,53,71,73–84 Its effectiveness in reducing the degree of PVL has been demonstrated in several studies (Figure 4A), with PVL reduced by at least one grade in ~70% of cases (Figure 4B).37,62,85–87 Therefore, BPD

remains an important step for resolving PVL but it is not without its risks, which must be understood by those performing TAVR procedures. In the following paragraphs we will discuss the risks of BPD and some technical aspects of the BPD procedure.

Potential Risks of Postdilation

Aortic Annulus Rupture/Aortic Damage

Aortic annular rupture remains a thankfully uncommon complication (<1%), but it is potentially fatal and accounts for ~14% of surgical bailout procedures during TAVR.88 LVOT calcification and excessive valve oversizing (>20%) have been identified as risk factors.89,90 BPD has been identified as a cause of aortic annular rupture in a number of case series and studies.89,91,92 In a multicentre study by Barbanti et al. of 31 consecutive patients with annular rupture matched to 31 controls, balloon dilation had been undertaken in 22% of those with annular rupture versus 0% in the control group (p=0.005).89 However, no differences in major aortic complications and no episodes of aortic annular rupture were seen by Daneault et al., who studied patients included in the PARTNER and PARTNER 2 trials who underwent BPD.93 In an analysis of patients undergoing postdilation with the CoreValve system, Harrison et al. did not find any statistically significant differences in major vascular complications between those who did and did not require BPD, although three intraprocedural deaths occurred, due to annulus rupture, cardiac perforation and iatrogenic ventricular septal defect in the BPD group.53

Stroke

Cerebrovascular events have been linked to the requirement for BPD. Given that BPD is more commonly required in severely calcified valves and is supported by transcranial studies, dislodgement and embolisation of particulate matter during BPD is most likely the cause of these events.35 Nombela-Franco et al., in their study of 211 patients undergoing TAVR with a balloon-expandable valve, found an increased rate of acute cerebrovascular events in the first 24 hours in those requiring postdilation (8.5% versus 0.7%, p<0.007), with no difference between groups beyond 24 hours (postdilation versus no postdilation, 3.4% versus 1.3%, p=0.312).37 This was further explored in a multicentre registry study of 1,061 patients receiving both balloon-expandable and self-expandable valves, which again found BPD to be associated with cerebrovascular events, with an almost 2.5-fold increased risk in patients undergoing BPD.33 A 1.85-fold increased risk was also found in the EVERY-TAVI registry, again a registry of both balloon and self-expandable TAVR valves.94 Similarly, in a propensity

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Balloon Pre-dilation and Post-dilation in TAVR Figure 4: Balloon Postdilation and Paravalvular Leak A. Effect of BPD on PVL 100 90

B. Reduction in PVL by at least one grade after BPD

80 58

60 50 40 30

91 71

10 0

Percentage

100

80 70

60 50 40 30 20 10

Pre Post

Takagi et al.62

Nombela-Franco et al.37

*Schultz et al.86

†Lasa et al.85

Watanabe et al.87

Grade 3–4

Grade 2

Takagi et al.62

Schultz et al.86

NombelaFranco et al.37

Watanabe et al.87

Study

Grade 0–1

*Study by Schultz et al. provides data on PVL ≤grade 2 without subdivision into grade 0–1.86 †Study by Lasa et al. provides data on PVL ≥grade 2 without subdivision into grade 3–4.85 BPD = balloon postdilation; PVL = paravalvular leak.

score-matched analysis, Goel et al. demonstrated an almost fivefold increased risk of 30 day stroke or transient ischaemic attack in those requiring postdilation after a balloon-expandable TAVR (HR 4.95; 95% CI [1.02–24.03]; p=0.04), and analysis of those requiring BPD in the PARTNER trial also demonstrated an increased risk of stroke in the first 7 days after the procedure (for those requiring BPD versus no BPD, 4.9% versus 2.6%, p=0.04).47,95 Analysis of the CoreValve US clinical trials, however, did not find any difference in cerebrovascular events in those requiring BPD.53 Given the devastating consequences of stroke, minimising the need for postdilation by reducing PVL rates is of paramount importance. Accurate sizing of the annulus using multidetector CT has come some way in eliminating the need for postdilation of the implanted TAVR and should be advised for all cases of elective TAVR.

Conduction Disorders

Postdilation is another potential insult to the conduction system after valve deployment that could theoretically increase the risk of conduction disorders. However, the link between BPD and conduction disorders is weak and studies specifically evaluating this association are very limited. A tendency towards higher rates of LBBB in those requiring postdilation was found by Nombela-Franco et al., but with no differences in new PPM rates for patients receiving balloon-expandable Sapien valves.37 Analysis of the PARTNER and PARTNER 2 trials also did not find higher PPM rates in those requiring postdilation, nor did analysis of the CoreValve US clinical trials.53,93 However, Barbanti et al., in an analysis of 1,376 patients receiving CoreValve prosthesis, 19.8% of whom had undergone BPD, found a nonsignificant trend towards increased PPM requirement in those requiring BPD (29% versus 22.7%, p=0.092).71 Nonetheless, for patients with other risk factors for conduction disorders and pacemaker requirement, the risks of BPD must be balanced against the benefits.

Prosthesis Damage

Expansion of a TAVR prosthesis beyond its nominal size has the potential to cause damage to the pericardial leaflets, to the stent frame or, in the case of significant over-expansion, to lead to central aortic regurgitation. In a multicentre study by Armijo et al. of patients with large and extralarge annuli, the majority of whom required over-expansion of the TAVR prostheses either by addition of extra volume to the prosthesis balloon or by performing aggressive BPD, the incidence of central aortic regurgitation

was 1.4%.96 During follow-up, postdilation was not associated with early valve degeneration or differences in valve gradients, however, there are no studies with long follow-up (>5 years) that specifically report the effects of BPD on valve haemodynamics. The potential damage to the prosthesis in the case of an aggressive BPD should be balanced against the potential positive effect of BPD in an underexpanded stent frame. In cases of significant underexpansion of the prosthesis, distortion of leaflet coaptation may have a negative impact on valve degeneration. Thus, BPD could be justified and have a beneficial effect on the prevention of valve deterioration.

Valve Embolisation

Valve embolisation can be a devastating complication of TAVR and is associated with higher mortality and major stroke at 30 days.97,98 A recent large multicentre study across 26 centres by Kim et al. found the incidence of valve embolisation to be 0.29%.98 Although malposition and device manipulation were the most common causes of embolisation, BPD was found to be the cause in 6.5% of cases of embolisation to the aorta and 3.6% of cases of ventricular embolisation.98 Makkar et al. also found postdilation to be one of the procedural causes of embolisation with the CoreValve prosthesis.97 The risk of embolisation must therefore be taken into account, especially if other risk factors exist such as suboptimal valve positioning.

General Recommendations on Postdilation

Given that no specific guidelines exist regarding postdilation, this section will outline the approach to BPD at our institution. The detrimental effects of PVL on outcomes have been clearly delineated.68–72 Our practice therefore is to perform both aortography and transthoracic echocardiography (transoesophageal only in complex anatomy) immediately after deployment of the device and, if valve position is correct, to perform BPD in all cases of grade III–IV PVL and to consider the risks and benefits of BPD in the context of grade II PVL. In younger, low-risk patients for whom optimal, durable results are vital, more aggressive postdilation approaches may be considered in the context of grade I–II PVL. In these scenarios, we perform BPD starting with semi-compliant balloons with a diameter equal to the mean annular diameter as measured on pre-TAVR CT and increase the balloon size according to the result. In the less frequent cases of high mean gradient (>20 mmHg) or frame underexpansion, we perform BPD to

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Balloon Pre-dilation and Post-dilation in TAVR optimise the effective orifice area and reduce valve gradients. We usually start with a semi-compliant balloon size equal to the perimeter-derived diameter or mean aortic annulus diameter, and subsequently larger, if needed, after a careful assessment of the result. In the context of valve-invalve procedures, we have adopted the approach of bioprosthesis fracture (if possible) with the aim of a mean gradient of <15–20 mmHg. In this context, non-compliant balloons are preferred with a size equal to, or slightly larger (~1 mm) than, the labelled diameter of the surgical bioprosthesis, and this has been shown to be effective in fracturing the bioprosthesis in a number of bench, and clinical studies.52,99–101 Our practice is to perform postdilation, as opposed to predilation for valve-in-valve TAVR. Although there are advantages and disadvantages to both, our experience suggests that there is less haemodynamic instability if postdilation and bioprosthesis fracture are performed in preference to predilation.

Conclusion

TAVR has revolutionised the treatment of symptomatic severe aortic stenosis with an exponential growing market. Successive iterations of TAVR valves have resulted in improved patient outcomes with comparable results to surgical aortic valve replacement even in 1. Leon MB, Smith CR, Mack M, et al. Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. https:// doi.org/10.1056/NEJMoa1008232; PMID: 20961243. 2. Martin GP, Sperrin M, Bagur R, et al. Pre-implantation balloon aortic valvuloplasty and clinical outcomes following transcatheter aortic valve implantation: a propensity score analysis of the UK Registry. J Am Heart Assoc 2017;6:e004695. https://doi.org/10.1161/JAHA.116.004695; PMID: 28214795. 3. Grube E, Naber C, Abizaid A, et al. Feasibility of transcatheter aortic valve implantation without balloon predilation: a pilot study. JACC Cardiovasc Interv 2011;4:751–7. https://doi.org/10.1016/j.jcin.2011.03.015; PMID: 21777882. 4. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol 2011;57:253–69. https://doi.org/10.1016/j.jacc.2010.12.005; PMID: 21216553. 5. Dumonteil N, Terkelsen C, Frerker C, et al. Outcomes of transcatheter aortic valve replacement without predilation of the aortic valve: insights from 1544 patients included in the SOURCE 3 registry. Int J Cardiol 2019;296:32–7. https:// doi.org/10.1016/j.ijcard.2019.06.013; PMID: 31256993. 6. Schymik G, Rudolph T, Jacobshagen C, et al. Balloonexpandable transfemoral transcatheter aortic valve implantation with or without predilation: findings from the prospective EASE-IT TF multicentre registry. Open Heart 2019;6:e001082. https://doi.org/10.1136/ openhrt-2019-001082; PMID: 31673387. 7. Fiorina C, Maffeo D, Curello S, et al. Direct transcatheter aortic valve implantation with self-expandable bioprosthesis: feasibility and safety. Cardiovasc Revasc Med 2014;15:200–3. https://doi.org/10.1016/j.carrev.2014.03.005; PMID: 24746865. 8. Pagnesi M, Kim WK, Conradi L, et al. Impact of predilatation prior to transcatheter aortic valve implantation with the selfexpanding Acurate neo device (from the Multicenter NEOPRO registry). Am J Cardiol 2020;125:1369–77. https:// doi.org/10.1016/j.amjcard.2020.02.003; PMID: 32098656. 9. Toutouzas K, Latsios G, Stathogiannis K, et al. One-year outcomes after direct transcatheter aortic valve implantation with a self-expanding bioprosthesis. A two-center international experience. Int J Cardiol 2016;202:631–5. https://doi.org/10.1016/j.ijcard.2015.09.075; PMID: 26451789. 10. Liao YB, Meng Y, Zhao ZG, et al. Meta-analysis of the effectiveness and safety of transcatheter aortic valve implantation without balloon predilation. Am J Cardiol 2016;117:1629–35. https://doi.org/10.1016/j. amjcard.2016.02.036; PMID: 27026641. 11. Auffret V, Regueiro A, Campelo-Parada F, et al. Feasibility, safety, and efficacy of transcatheter aortic valve replacement without balloon predilation: a systematic review and meta-analysis. Catheter Cardiovasc Interv 2017;90:839–50. https://doi.org/10.1002/ccd.27040; PMID: 28403562. 12. Ferrera C, Nombela-Franco L, Garcia E, et al. Clinical and

lower risk patients. Valve durability becomes a major focus as we move into the low-risk patient profile group. As such, refinements in TAVR technique and optimisation of results are a priority. Although simplified TAVR procedures are now commonplace, this must not be at the expense of optimal results. As such, pre- and post-dilation of TAVR valves are likely to remain important adjunctive procedures for optimisation of the prosthesis and ensuring its durability. As outlined in this review, each has its place, with predilation facilitating native valve crossing with the prosthesis, ensuring uniform expansion of the prosthesis and reducing PVL; this comes at the expense of an increased risk of haemodynamic instability and conduction disorders. Postdilation too has a number of advantages, such as reducing PVL, correcting any frame underexpansion and optimising transvalvular gradients, but again there is a trade-off with the increased risk of stroke, valve embolisation or leaflet damage, conduction disorders and annular rupture. The risks and benefits as outlined in this review should be kept in mind when deciding in whom these procedures are required. With the huge strides in the TAVR field over the last decade, it is likely that the coming decade will also bring many changes to how TAVR is performed, highlighting the constant need to evaluate new data as they become available.

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Structural

Is This the Prime Time for Transradial Access Left Ventricular Endomyocardial Biopsy? Zaccharie Tyler ,1 Oliver P Guttmann ,1,2 Konstantinos Savvatis ,1,2 Daniel Jones

and Constantinos O’Mahony

1,2

1. St Bartholomew’s Hospital, London, UK; 2. UCL Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK

Abstract

Left ventricular endomyocardial biopsy (EMB) is an essential tool in the management of myocarditis and is conventionally performed via transfemoral access (TFA). Transradial access EMB (TRA-EMB) is a novel alternative and the authors sought to determine its safety and feasibility by conducting a systematic review of the literature. Medline was searched in 2020, and cohort demographics, procedural details and complications were extracted from selected studies. Four observational studies with a combined total of 496 procedures were included. TRA-EMB was most frequently performed with a sheathless MP1 guide catheter via the right radial artery. The most common complication was pericardial effusion (up to 11% in one study), but pericardial drainage for tamponade was rare (one reported case). Death and mitral valve damage have not been reported. TRA-EMB was successful in obtaining samples in 99% of reported procedures. The authors concluded that TRA-EMB is a safe and feasible alternative to TFA-EMB and the most common complication is uncomplicated pericardial effusion.

Keywords

Transradial approach, myocarditis, biopsy Disclosure: The authors have no conflicts of interest to declare. Availability of data: Data are available on request from the corresponding author. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Received: 11 June 2021 Accepted: 24 August 2021 Citation: Interventional Cardiology 2021;16:e29. DOI: https://doi.org/10.15420/icr.2021.20 Correspondence: Constantinos O’Mahony, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK. E: drcostasomahony@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Endomyocardial biopsy is an important diagnostic tool in the workup of patients with non-ischaemic cardiomyopathy. In recent years, left ventricular endomyocardial biopsy (LVEMB) has supplanted right ventricular endomyocardial biopsy as the method of choice for obtaining cardiac tissue.1–3 A recent expert consensus paper describes how, when selecting patients for endomyocardial biopsy (EMB), it is important to identify candidates for whom biopsy can provide information that will aid their management. Appropriate circumstances include clinically suspected myocarditis, decompensation in dilated cardiomyopathy, toxicity from cancer therapy, unexplained ventricular arrhythmias/conduction disorders, heart failure in autoimmune disorders that is unresponsive to treatment, unexplained restrictive or hypertrophic cardiomyopathy and cardiac tumours.4 LVEMB is conventionally undertaken via the transfemoral route but the radial artery has become the access route of choice for most coronary interventions and diagnostic procedures because it has lower complication rates, allows earlier mobilisation and reduces hospital stay.5,6 However, adoption of the transradial route for LVEMB has been slow, partly owing to the larger diameter catheters used to accommodate bioptomes.7–16 In recent years, more data are emerging demonstrating that the transradial route is not only safe but also allows the operator to collect sufficient specimens, as well as being less restrictive for patients.

The aim of this study was to systematically review the literature for the complications and feasibility of transradial access endomyocardial biopsy (TRA-EMB).

Protocol and Registration

The systematic review was carried out in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses amendment (PRISMA) to the Quality of Reporting of Meta-analyses (QUOROM) statement and Cochrane Collaboration and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. The systematic review protocol was not registered. All authors read, critically appraised, provided feedback and approved the final manuscript. PubMed was searched, and the reference lists of reviews, letters and editorials were scrutinised for relevant material.

Inclusion and Exclusion Criteria

All studies, irrespective of setting, were considered. Only adult patients (≥16 years of age) undergoing TRA-EMB were considered.

Search Strategy

The Medline search strategy was: endomyocardial AND (radial OR transradial). Only articles in English were included for the analysis and relevant titles in other languages were recorded. The search was undertaken in November 2020.

Transradial Access Left Ventricular Endomyocardial Biopsy Synthesis of Results and Summary of Measures

Figure 1: Study Selection Identification

Records identified through database searching n=41

Screening

Additional records identified through other sources n=0

Records after duplicates excluded n=41 Records screened n=41

Records excluded n=32

Eligibility

Full text articles assessed for eligibility n=9

Full text articles excluded n=5*

Inclusion

Studies included in the review n=4

*One editorial and four observational studies were excluded: the original experience of Schulz et al. was excluded because Göbel et al. (included) was recently updated; Choudhury et al., Schaufele et al. and Nobre Menezes et al. were excluded as the patients were reported in Choudhury et al. (included).8,9,12,13,15,16

Study Records

Data management and selection

The initial literature search results were uploaded to EndNote (Clarivate Analytics), which was used to manage the retrieved abstracts. The retrieved studies were independently reviewed at title and/or abstract level for inclusion and exclusion criteria. Full manuscripts were obtained for all reports meeting the inclusion criteria or when there was ambiguity. The full manuscripts were then reviewed to see if the inclusion criteria were met. A detailed study of authors, dates and locations was used to reduce redundancy. The reviewers were not blinded to the journal titles or to the study authors or institution. Reasons for exclusion were documented.

The extracted data from each study were tabulated and presented descriptively.

Results

A total of 41 articles fulfilled the search criteria in PubMed (Figure 1) and four observational studies were selected for the systematic review: Kherad et al., Choudhury et al., Tyler et al. and Göbel et al. (Table 1).11,13,14,16 The studies include mostly male patients in their fifth or sixth decade of life from Europe, North America and Japan.

Methodological Quality of the Studies

All studies were found to be at low risk of bias. Kherad et al. and Choudhury et al. were awarded eight affirmative answers, while Tyler et al. and Göbel et al. were awarded nine affirmative answers out of 10.11,13,14,16

TRA-EMB Technique

Right radial access (RRA) was used in Tyler et al.,14 Choudhury et al.13 and Kherad et al.11 Göbel et al.16 did not report which radial artery was used. All reports used the same procedural technique albeit with different equipment. Briefly, once transradial access had been gained, a pigtail catheter was inserted into the guide catheter of choice and used to cross the aortic valve. Once in the left ventricle (LV), the guide catheter is advanced over the pigtail to the mid-LV cavity and the pigtail catheter is then removed. Guide catheter position is confirmed using fluoroscopy in orthogonal views. The bioptome is then used to take the tissue sample. Heparin is given during the procedure to prevent periprocedure strokes and radial artery occlusion. Most studies used sheathless MP1 guides with a wide variety of bioptomes (Table 1).

Complications of TRA-EMB

Data collection

Certain procedural complications were described consistently across all studies. These were pericardial effusion (requiring no intervention, or requiring pericardiocentesis or transfusion), VF, stroke or transient ischaemic attack, mitral valve injury, crossover to right femoral access and death (Figure 2).

Data Items

The most common complication was pericardial effusion, with an incidence of up to 11.1% in Göbel et al.16 However, the vast majority of these were transient and required no intervention. Tamponade requiring pericardiocentesis is uncommon, with a single case recorded by Tyler et al.14

Data were extracted from the full-length manuscripts and transcribed to a spreadsheet (Excel, Microsoft). Demographic data and methodological characteristics were collected. For each article, the name of the first author, year of publication, country of origin, number of centres included and study design were extracted. Patient variables, including the method of EMB were also retrieved. For each study, the following complications were extracted: bleeding requiring blood transfusion; pericardial effusion; cardiac tamponade requiring treatment; VF; cerebrovascular accident; crossover to transfemoral access (TFA); mitral valve injury; and death. Also retrieved were mean numbers of specimens obtained.

Assessing Methodological Quality

The Joanna Briggs Institute critical appraisal tool for case series was used. Two independent reviewers assessed the eligible studies, with a third reviewer adjudicating if no decision could be reached. Each article was scored on 10 questions. If ‘yes’ was the answer to half or more of the questions, the study was classified as having a low risk of bias; if ‘no’ was answered to half or more of the questions, it was classified as having a high risk of bias; and, if the answer to half or more of the question was ‘unclear’, the risk of bias could not be assessed.

Crossover to right femoral access was described in three out of the four studies, most commonly owing to access site complications, for example severe radial artery spasm or haematoma.13,14,16 Three patients out of the 496 reported cases crossed over to transfemoral access. Only one occurrence of VF was reported; the patient was immediately cardioverted.9,16 Two patients developed procedure-related stroke but the level of disability is not reported.9,16 No occurrences of mitral valve injury or death were described in any of the studies. Access site complications were reported in two studies. In Kherad et al., all patients had US Doppler of the radial artery performed 24 hours after the procedure, which showed occlusion in 50%.11 Two-thirds of patients with an occlusion had a ‘palpable radial pulse’ that was actually an ulnar pulsation transmitted via the palmar arch, but none required further intervention. Choudhury et al. reported mild to moderate radial artery spasm in 10% of patients.13

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Transradial Access Left Ventricular Endomyocardial Biopsy Table 1: Studies Included in the Systematic Review Authors

Kherad et al.11

Choudhury et al.13

Tyler et al.14

Göbel et al.16

Publication date

2016

2019

2020

Centres

Prospective/retrospective

Prospective

Retrospective

Enrolment dates

January 2015 to July 2015

Not stated

September 2016 to October 2019

November 2013 to December 2018

Location

Berlin (Germany)

London (Canada), Stuttgart (Germany), Yokkaichi (Japan), Lisbon (Portugal)

London (UK)

Mainz (Germany)

Cohort overlap

Independent cohort

Update of Choudhury et al. 2018;12 includes Schaufele et al. 20158 and partially includes Menezes et al. 202015

Independent cohort

Update of Schulz et al. 20159

Number of patients

130 (134)

25 (25)

323 (138)

Male (%)

62 (73)

72 (56)

73 (64)

Age (years) mean

56 (44)

48 (46)

56 (53)

Guide catheter used

7.5 Fr sheathless MP1

7.5 Fr sheathless (83%) most commonly MP1

6 Fr MP1

7.5 Fr Sheathless MP1

Bioptome used

Medizintechnik, Meiners

Several different devices

Cordis 5.5 Fr 104 cm

Medwork 180 cm

Success rate (% of patients with biopsy obtained)

100

99 (100)

88 (96)

99 (100)

Minimum number of specimens required

Not stated

3 (3)

Not stated

Mean number of specimens obtained

6.8 (6.1)

4 (5)

7 (7)

Blood transfusion (%)

0 (0)

4 (0)

0 (0)

Pericardial effusion (%)

3.1 (10)

8 (4)

11.1 (7.4)

Tamponade/drain (%)

0 (0)

4 (4)

0 (0)

VF (%)

0 (0)

0.3 (0)

CVA (%)

0 (0)

0.6 (0.7)

Crossover to RFA (%)

1.0

4 (4)

0.3

Mitral valve injury (%)

0 (0)

0 (0.7)

Death (%)

0 (0)

Three studies included cohorts of patients who underwent transfemoral LVEMB for comparison. Values for these cohorts are given in brackets. CVA = cerebrovascular accident; RFA = right femoral access.

EMB Specimens Retrieved and Procedural Success

The mean number of specimens in each cohort ranged from four to 10. Samples were obtained in most patients, with procedural success ranging between 88% to 100% (Table 1).

Discussion

This systematic review summarises the up-to-date global experience of TRAEMB and demonstrates it is a feasible and safe alternative to TFA-EMB. The most common complication was pericardial effusion, which was managed conservatively in most cases. To date, procedural deaths and mitral valve injury have not been reported. TRA-EMB is a relatively new technique and the complication rates are expected to decline as experience increases. The data available for TRA-EMB were all derived from observational studies from multiple centres in Europe, Asia and North America. Assessment with the Joanna Briggs Institute critical appraisal tool demonstrated a low risk of bias but the indication for TRA-EMB was not clearly stated in the included studies. The most frequent complication was pericardial effusion without tamponade. The variability in prevalence (0–11%) may relate to the different monitoring strategies used in each centre. Göbel et al. reported

the highest incidence of pericardial effusion but all patients underwent echocardiography immediately and 24 hours after the procedure, increasing the chances of detecting a slowly developing effusion; other centres undertook only immediate post-procedural echocardiography.16 Other potential explanations for the high prevalence include the presence of a pre-procedure pericardial effusion and the retrospective nature of the study. The route of access may not play a major role in cardiac perforation as Göbel et al. used a cohort of TFA-EMB for comparison and there was no significant difference in the incidence of pericardial effusion (11.2% for TRA-EMB versus 7.4% for TFA-EMB; p=0.21).16 Furthermore, Choudhury et al. also included a TFA-EMB cohort and they reported a lower rate of pericardial effusion in the TRA-EMB group (3.1% for TRA-EMB versus 10.4% for TFA-EMB; p=0.018).13 These data suggest that there is no increased risk of pericardial effusion in TRA-EMB compared to TFA-EMB. In contrast to uncomplicated pericardial effusions, tamponade is uncommon during TRA-EMB, in keeping with experience from TFA-EMB (<1%).1,3 Other complications of TRA-EMB were less frequent. Göbel et al. was the only study where patients experienced procedure-related strokes,

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Transradial Access Left Ventricular Endomyocardial Biopsy Figure 2: Complications Reported in Association with Transradial Access Endomyocardial Biopsy 12

The desired number of biopsy samples varied across the four studies, with some describing a targeted ‘minimum sample number’ for each procedure. However, diagnostic-quality samples were obtained in the vast majority of procedures, with the overall success rate of TRA-EMB across the four studies being 98.99% (491 out of 496 procedures).

Prevalence (%)

Almost all TRA-EMB procedures were undertaken via the RRA given the standard set-up of the equipment in the lab, especially in obese patients.20 However, the left radial artery has anatomical advantages as the left subclavian artery arises directly from the aorta making the path traversed by the catheters similar to the transfemoral approach.21,22 In addition, upper limb arteries are more tortuous on the right than the left side, especially in the elderly people and left radial access TRA-EMB may further improve the procedure.23

8 6 4 2 0

Kherad et al. 201611 Transfusion

Choudhury et al. 201913 Effusion

Tyler et al. 202014 Tamponade

Göbel et al. 202016 VF

CVA

CVA = cerebrovascular accident.

but the rate of stroke was comparable to that in the TFA-EMB cohort (0.6% for TRA-EMB versus 0.7% for TFA-EMB; p=0.884).16 No deaths have been reported due to complications arising from TRA-EMB and the one occurrence of VF was successfully treated.16 Radial artery occlusion complicated 50% of cases and predictors of occlusion include female sex, diabetes, younger age and small radial artery diameter.11,17,18 While this does not affect the feasibility of the index procedure, it may play a role in patients who need repeat procedures.9,12 Using a standard sheath may help reduce the likelihood of radial artery occlusion.19 1. Yilmaz A, Kindermann I, Kindermann M, et al. Comparative evaluation of left and right ventricular endomyocardial biopsy. Circulation 2010;122:900–9. https://doi.org/10.1161/ CIRCULATIONAHA.109.924167; PMID: 20713901. 2. Frustaci A, Pieroni M, Chimenti C. The role of endomyocardial biopsy in the diagnosis of cardiomyopathies. Ital Hear J 2002;3:348–53; PMID: 12116798. 3. Chimenti C, Frustaci A. Contribution and risk of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period. Circulation 2013;128:1531–41. https://doi.org/10.1161/ CIRCULATIONAHA.114.009355; PMID: 25047591. 4. Seferović PM, Tsutsui H, McNamara DM, et al. Heart Failure Association of the ESC, Heart Failure Society of America and Japanese Heart Failure Society position statement on endomyocardial biopsy. Eur J Heart Fail 2021;23:854–71. https://doi.org/10.1002/ejhf.2190. https://doi.org/10.1002/ ejhf.2190; PMID: 34010472. 5. Mitchell MD, Hong JA, Lee BY, et al. Systematic review and cost-benefit analysis of radial artery access for coronary angiography and intervention. Circ Cardiovasc Qual Outcomes 2012;5:454–62. https://doi.org/10.1161/ CIRCOUTCOMES.112.965269; PMID: 22740010. 6. Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet 2011;377:1409–20. https://doi.org/10.1016/S01406736(11)60404-2; PMID: 21470671. 7. Bagur R, Bertrand OF, Beliveau P, et al. Feasibility of using a sheathless guiding catheter for left ventricular endomyocardial biopsy performed by transradial approach. J Invasive Cardiol 2014;26:E161–3; PMID: 25480998. 8. Schäufele TG, Spittler R, Karagianni A, et al. Transradial left ventricular endomyocardial biopsy: assessment of safety and efficacy. Clin Res Cardiol 2015;104:773–81. https://doi.

This study is limited by the small number of reported cases in the literature, which are derived from non-randomised studies.

Conclusion

TRA-EMB is a safe alternative to TFA-EMB. The most common complication is an uncomplicated pericardial effusion, which can be conservatively treated.

Clinical Perspective

• Left ventricular biopsy is usually performed via the femoral artery. • Transradial access is emerging as an alternative access route. • Transradial access allows diagnostic quality samples to be acquired in most cases.

• Uncomplicated pericardial effusions are the most common complication.

org/10.1007/s00392-015-0844-1; PMID: 25832352. 9. Schulz E, Jabs A, Gori T, et al. Feasibility and safety of left ventricular endomyocardial biopsy via transradial access: technique and initial experience. Catheter Cardiovasc Interv 2015;86:761–5. https://doi.org/10.1002/ccd.25834; PMID: 25586731 10. Bagur R, Gilchrist IC. Transradial approach to take a little piece of heart. Catheter Cardiovasc Interv 2015;86:766–7. https://doi.org/10.1002/ccd.26229; PMID: 26386240. 11. Kherad B, Köhncke C, Spillmann F, et al. Postprocedural radial artery occlusion rate using a sheathless guiding catheter for left ventricular endomyocardial biopsy performed by transradial approach. BMC Cardiovasc Disord 2016;16:253. https://doi.org/10.1186/s12872-016-0432-y; PMID: 27931184. 12. Choudhury T, Schäufele TG, Lavi S, et al. Transradial approach for left ventricular endomyocardial biopsy. Can J Cardiol 2018;34:1283–8. https://doi.org/10.1016/j. cjca.2018.05.007; PMID: 30078693. 13. Choudhury T, Lurz P, Schäufele TG, et al. Radial versus femoral approach for left ventricular endomyocardial biopsy. EuroIntervention 2019;15:678–84. https://doi.org/10.4244/eijd-18-01061; PMID: 30741639 14. Tyler Z, Guttmann OP, Dhinoja M, et al. The safety and feasibility of transitioning from transfemoral to transradial access left ventricular endomyocardial biopsy. J Invasive Cardiol 2020;32:e349–54; PMID: 33168780. 15. Nobre Menezes M, Infante Oliveira E, Costa e Silva A, et al. Transradial left ventricular endomyocardial biopsy feasibility, safety and clinical usefulness: Initial experience of a tertiary university center. Rev Port Cardiol 2020;39:453–60. https:// doi.org/10.1016/j.repc.2019.11.004; PMID: 32753337. 16. Göbel S, Schwuchow-Thonke S, Jansen T, et al. Safety of transradial and transfemoral left ventricular compared with transfemoral right ventricular endomyocardial biopsy. ESC Hear Fail 2020;7:4015–23. https://doi.org/10.1002/ ehf2.13006; PMID: 32949187.

17. Pancholy S, Coppola J, Patel T, Roke-Thomas M. Prevention of radial artery occlusion – Patent Hemostasis Evaluation Trial (PROPHET study): a randomized comparison of traditional versus patency documented hemostasis after transradial catheterization. Catheter Cardiovasc Interv 2008;72:335–40. https://doi.org/10.1002/ccd.21639; PMID: 18726956. 18. Uhlemann M, Möbius-Winkler S, Mende M, et al. The Leipzig prospective vascular ultrasound registry in radial artery catheterization: impact of sheath size on vascular complications. JACC Cardiovasc Interv 2012;5:36–43. https:// doi.org/10.1016/j.jcin.2011.08.011; PMID: 22230148. 19. Mohsen A, Alqasrawi M, Shantha GPS, et al. Comparison of radial artery occlusion following transradial access for percutaneous coronary intervention using sheath-based versus sheathless technique. Sci Rep 2018;8:12026 https:// doi.org/10.1038/s41598-018-30462-1; PMID: 30104697. 20. Kado H, Patel AM, Suryadevara S, et al. Operator radiation exposure and physical discomfort during a right versus left radial approach for coronary interventions: a randomized evaluation. JACC Cardiovasc Interv 2014;7:810–6. https://doi. org/10.1016/j.jcin.2013.11.026; PMID: 24954573. 21. Dominici M, Diletti R, Milici C, et al. Left radial versus right radial approach for coronary artery catheterization: a prospective comparison. J Interv Cardiol 2012;25:203–9. https://doi.org/10.1111/j.1540-8183.2011.00689.x; PMID: 22272568. 22. Kawashima O, Endoh N, Terashima M, et al. Effectiveness of right or left radial approach for coronary angiography. Catheter Cardiovasc Interv. 2004;61:333–7. https://doi. org/10.1002/ccd.10769; PMID: 14988891. 23. Dehghani P, Mohammad A, Bajaj R, et al. Mechanism and predictors of failed transradial approach for percutaneous coronary interventions. JACC Cardiovasc Interv 2009;2:1057– 64. https://doi.org/10.1016/j.jcin.2009.07.014; PMID: 19926044.

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Anterograde CTO Techniques

The Impact of Calcium on Chronic Total Occlusion Management Claudia Cosgrove ,1 Kalaivani Mahadevan ,2 James C Spratt

and Margaret McEntegart

1. St George’s University Hospitals NHS Foundation Trust, London, UK; 2. Bristol Heart Institute, Bristol, UK; 3. Golden Jubilee National Hospital, Glasgow, UK

Abstract

Coronary artery calcification is prevalent in chronic total occlusions (CTO), particularly in those of longer duration and post-coronary artery bypass. The presence of calcium predicts lower procedural success rates and a higher risk of complications of CTO percutaneous coronary intervention. Adjunctive imaging, including pre-procedural computed tomography and intracoronary imaging, are useful to understand the distribution and morphology of the calcium. Specialised guidewires and microcatheters, as well as penetration, subintimal entry and luminal re-entry techniques, are required to cross calcific CTOs. The use of both atherectomy devices and balloon-based calcium modification tools has been reported during CTO percutaneous coronary intervention, although they are limited by concerns regarding safety and efficacy in the subintimal space.

Keywords

Chronic total occlusion, coronary artery calcium, intracoronary imaging, microcatheters, subintimal space, re-entry, atherectomy Disclosure: The authors have no conflicts of interest to declare. Received: 5 January 2021 Accepted: 19 July 2021 Citation: Interventional Cardiology 2021;16:e30. DOI: https://doi.org/10.15420/icr.2021.01 Correspondence: Claudia Cosgrove, St George’s University Hospitals NHS Foundation Trust, Tooting, London SW17 0QT, UK. E: cscosgrove@yahoo.com.au Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Advances in technique and technology have increased procedural success and improved outcomes in chronic total occlusion (CTO) percutaneous intervention (PCI).1 These challenging cases are made all the more so by the presence of coronary arterial calcification, which is prevalent in CTOs, and an independent predictor of procedural success and complications.2–5 Specific techniques and equipment can be utilised to identify, quantify and overcome the procedural obstacles caused by calcium within CTOs.

than in non-grafted occlusions exposed to the lower pressures of the collateral circulation.7 Interestingly, these vessels are less likely to have significant negative remodelling compared with non-calcified non-grafted CTO vessels, possibly due to the calcium acting as a scaffold to prevent vasoconstriction.7

Pathophysiology of Calcium in Chronic Total Occlusion

Calcium is prevalent in CTOs. On virtual histology intravascular ultrasound (IVUS) analysis, Guo et al. reported that 64% of CTOs contained predominantly fibrocalcific plaque.10 In a retrospective study of 1,476 consecutive CTO PCIs in 1,453 patients in the US, moderate or severe calcium, as assessed by coronary angiography, was present in 58% of occlusions.11 Patients with these calcified occlusions were older and had more comorbidities including diabetes, hypertension, peripheral vascular disease, left ventricular systolic dysfunction and renal impairment.11 Similarly, the PROGRESS registry, Japanese Multicentre registry and a substudy of patients in the Japanese registry undergoing retrograde CTO PCI reported 57–59% of CTOs had angiographically moderate or severe calcification.2,3,12

Early in the development of a CTO, the plaque is predominantly soft/lipidic, with organising thrombus, cholesterol-laden cells, foam cells and loose fibrous tissue (Figures 1A and 1B). As the occlusion ages, the composition typically becomes more dense, with fibrous tissue and calcific deposits (Figure 1C).6 Thus, longer duration CTOs are more heavily calcified than those of shorter duration.7 Following coronary artery bypass grafting (CABG), there is accelerated progression of atherosclerosis in the native coronary arteries. Possible mechanisms for this include blood stasis and low shear stress due to competitive flow from the grafts.8 The development of a new CTO in an artery post-bypass is common, occurring in 43% of patients within the first postoperative year.9 CTOs in post-CABG patients are of higher complexity, characterised by more extensive and severe calcification than those in non-bypassed vessels. While calcium is most commonly located at the proximal cap of a CTO, post-CABG it is frequently present in the adjacent proximal and distal vessel, within the CTO segment, and at the distal cap.7 Unique to the post-CABG circulation, the CTO distal cap is exposed, via the bypass graft, to aortic pressure, and thus is more likely to be calcified

Incidence and Epidemiology of Calcium in Chronic Total Occlusion

Success and Safety in Calcific Chronic Total Occlusion

The presence of significant calcification within a CTO has repeatedly been shown to be an independent predictor of PCI success and complications, and thus calcium is a key component of the CTO complexity scores.2,4,5 Other adverse anatomical characteristics often coexist, with calcific occlusions more likely to be longer, tortuous and to have an ambiguous proximal cap.11

The Impact of Calcium on CTO Management Figure 1: Chronic Total Occlusion Histology

A: Chronic total occlusion with organising thrombus; B: Proteoglycan-rich chronic total occlusion; C: Calcified chronic total occlusion. Source: Sakakura et al.7 Reproduced with permission from Oxford University Press.

Figure 2: CT Coronary Angiography of Calcific Chronic Total Occlusion

most frequent complication is perforation with tamponade due to the requirement for aggressive calcium modifications techniques.11

Imaging of Coronary Calcium in Chronic Total Occlusion

Coronary angiography has a high specificity, but low sensitivity, for detecting calcium, and does not provide information about its morphology or distribution within the plaque and vessel wall.16 CT coronary angiography (CTCA) has higher sensitivity and specificity than coronary angiography for detecting, quantifying and assessing the distribution of calcium, in addition to providing a more accurate measure of occlusion length (Figure 2). While the use of CTCA for procedural planning has been associated with improved CTO PCI success rates, an occlusion length >15 mm and calcification involving >50% of the vessel wall on cross-sectional imaging are independent predictors of procedural failure.17–19

CT coronary angiogram demonstrating severe calcification of the proximal and distal caps. Source: Spratt et al.37 Reproduced with permission from Optima Education.

In a subset of patients from the PROGRESS registry in whom initial CTO PCI was unsuccessful and who underwent subintimal plaque modification (or a ‘modification procedure’), the prevalence of moderate or severe calcification was 73%.13 In a Japanese cohort of patients who underwent CTCA prior to attempted CTO PCI, 50% of those for whom the attempt was unsuccessful had severe calcification identified on CTCA, compared with 16% of those for whom the procedure was successful.14 When CTO PCI was successful in these cases, severe calcification was associated with higher rates of restenosis and re-occlusion. The presence of significant calcification hinders the wire-based strategies for crossing an occlusion, with dissection and re-entry techniques often necessary.11 In a Japanese study of antegrade wiring, calcification of the CTO was found to be the most powerful predictor of procedural failure, with an odds ratio of 2.5.15 In addition, moderate or severe calcification is associated with longer procedure duration, higher radiation doses, larger contrast volumes and a higher incidence of major adverse cardiac events (3.7% versus 1.8%) compared with mild or non-calcified CTOs. The

Intracoronary imaging is an essential tool for calcium assessment during CTO PCI. With the desire to avoid extending or expanding extra-plaque tracks through the subintimal space (SIS) by injecting contrast as required for optical coherence tomography, IVUS is usually preferred. In calcified CTOs, IVUS is useful at several stages during the PCI procedure. It can be used to determine the location and the degree of calcification of the proximal cap (Figure 3), when this is angiographically ambiguous. After crossing an occlusion, IVUS can be used to assess the morphology and distribution of calcium, to determine the optimal mode of calcium modification, and then to confirm adequate modification prior to stent implantation. Finally, it can be used for stent optimisation and to measure stent expansion.20 Following dissection and re-entry with extra-plaque stenting, eccentric stent expansion is common due to the displacement of calcific plaque within the vessel structure. In these cases, a pragmatic approach should be adopted as to what constitutes an acceptable stent result, as overzealous post-dilatation has the potential to cause perforation. As in non-CTO PCI, the absolute stent expansion, quantified as minimum stent area is the most important predictor of long-term stent patency.20

Procedural Challenges in Calcific Chronic Total Occlusion Percutaneous Intervention Lesion Crossing

A procedural set-up with large-calibre supportive guide catheters, a guide extension or an anchor balloon is particularly important when treating calcified CTOs.

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The Impact of Calcium on CTO Management Figure 3: Calcific Proximal Cap on Intravascular Ultrasound

Intravascular ultrasound demonstrating a calcific proximal cap (circled). Source: Spratt et al.37 Reproduced with permission from Optima Education. IVUS = intravascular ultrasound. IVUS demonstrating a calcific proximal cap.

Calcium is most commonly located at the proximal cap, resulting in difficulty with wire and microcatheter crossing. Low or medium penetration force wires are unlikely to cross the cap and may deflect into the SIS. If an antegrade wiring strategy is intended, escalation to a high penetration force wire will be required to cross the cap. After the most resistant segment has been negotiated, de-escalation to a lower penetration force wire is recommended to reduce the risk of wire exit. When there is also calcium within the occlusive segment or at the distal cap, further wire escalation and de-escalation may be required. Coil-based and penetrative microcatheters can facilitate crossing of calcific occlusions. Coil-based microcatheters, such as the Corsair (Asahi Intecc), Mamba (Boston Scientific) and Turnpike Spiral (Teleflex) have internal and/or external coils that allow torque to be applied, to assist propagation through calcific or tortuous segments. The Turnpike Spiral has the addition of distal external threads, which grip resistant plaque to aid crossing, while the Turnpike Gold (Teleflex) has a metallic threaded tip designed to engage and penetrate the proximal cap or calcific plaque. Caution should be taken in long segments of severe calcific disease where the spiral thread or gold metallic tip have the potential to lock into the lesion, making them difficult to remove. The Tornus (Asahi Intecc) is an alternative stiffer metallic catheter with exposed wrapped wires, which is torqued with anti-clockwise rotation. Intentional balloon rupture, balloon-assisted microdissection or ‘grenadoplasty’, can be useful to facilitate delivery of equipment through the proximal cap or beyond a calcified segment. A small balloon is engaged into the plaque and inflated to high pressure to cause balloon rupture, resulting in hydraulic disruption and weakening of the plaque. When a wiring strategy with intraplaque crossing is not feasible due to calcification, dissection techniques can be employed by deliberately entering and traversing the SIS, going extraplaque around the calcific

occlusion and re-entering the lumen beyond the distal cap. Entry into the SIS can occur while attempting to penetrate the proximal cap or by using specific techniques (e.g. scratch and go, balloon-assisted subintimal entry, power knuckle, contrast-induced hydraulic dissection; Figure 4).21 Antegrade dissection re-entry is usually performed using the CrossBoss/ Stingray system (Boston Scientific). The delivery of equipment and re-entry into the distal lumen can be difficult in the presence of calcium, but can be facilitated by the support of a guide extension and high penetration force wires. In retrograde dissection re-entry, knuckle wires are used to track through the SIS in both an antegrade and retrograde manner, until they become overlapped. The two extraplaque tracks are then connected by performing balloon dilatation to expand the antegrade SIS, allowing passage of a retrograde wire into the antegrade guide extension or catheter.

Plaque Modification

Adequate lesion preparation and calcium modification is essential prior to stent implantation to prevent stent underexpansion, the strongest predictor of early stent thrombosis and restenosis.22,23 This is particularly important in CTO PCI, with longer stented segments increasing the risk of restenosis, and with subintimal stenting following dissection re-entry techniques. Where possible, IVUS should be used to assess calcium modification prior to stenting, and to confirm adequate stent expansion. Pre-dilatation is routinely performed with non-compliant balloons. When this is inadequate, an ultra-high-pressure balloon (SIS Medical), cutting balloon with longitudinal atherotomes or scoring balloons with an external element can facilitate fracturing and disruption of the calcific plaque.24 While these modifying balloons have been used both intraplaque and extraplaque during CTO PCI, it is anticipated that there will be an associated increased risk of perforation.

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The Impact of Calcium on CTO Management Figure 4: Balloon-assisted Subintimal Entry BASE technique

BASE + power knuckle 1. Balloon inflated in proximal vessel (close to CTO) creates intimal disruption facilitating access into the subintimal space

+ 3. Inflating a co-axial anchor balloon traps the microcatheter providing additional support to advance the knuckle past the proximal cap

2. Microcatheter is positioned proximal to the area of disruption and a soft polymer with an umbrella-shaped tip is advanced into the subintimal plane Balloon-assisted subintimal entry technique. BASE = balloon-assisted subintimal entry; CTO = chronic total occlusion. Source: Spratt et al.37 Reproduced with permission from Optima Education.

The intravascular lithotripsy balloon (Shockwave Medical) delivers sonic pressure waves to selectively fracture calcium deep into the vessel wall and improve compliance prior to stent implantation.25 While it has been demonstrated to be safe and effective in non-occlusive calcific disease, to date there is one case series and several case reports of its use during CTO PCI, both intraplaque and extraplaque following CTO crossing, for in-stent occlusion, to facilitate connection between the antegrade and retrograde SIS during retrograde dissection re-entry, and during modification procedures.26–30

RA cases in the substudy of the PROGRESS registry, but did not occur in any RA cases in other, smaller case series.32,33,35

In up to 7% of CTOs, failure to cross with a balloon occurs after successful guidewire crossing.31,32 In such balloon uncrossable lesions, when there is inadequate dilatation with modifying balloons, or when treating a long segment of severe calcium, rotational atherectomy (RA) may be indicated. With a microcatheter across the occlusion, this can be used to exchange for the RotaWire. RA has been reported in case series to be safe and effective during CTO PCI, with the use of a small burr advised to reduce the risk of perforation.32–35 Occasionally, if other techniques for proximal cap crossing fail, RA can be used for cap modification. In this scenario, the RotaWire is advanced as far as possible beyond the cap into the occlusion or SIS, and a focused pecking motion of the burr is used.

Excimer laser coronary atherectomy generates vapour bubbles to cause the molecular breakdown of tissue. It can be useful to treat uncrossable proximal caps or occlusive segments, balloon undilatable lesions and occlusive in-stent restenosis. It is less available and used less frequently than RA or orbital atherectomy. In a cohort of 18 cases in which excimer laser coronary atherectomy was used alone or in combination with RA during CTO PCI (all of which were antegrade wire escalation), procedure success was achieved in 89%, with no perforations or other laser-related complications.36 It is anticipated that the use of ECLA extraplaque would carry a prohibitive risk of causing perforation of the adventitia.

RA use in CTO PCI is uncommon, reported in approximately 3% of cases.33,35 Patients requiring RA tend to be older, with a higher prevalence of diabetes, left ventricular dysfunction and previous CABG. In the majority of reported cases, the CTO was crossed by antegrade wiring and RA performed intraplaque, with the indication equally divided between failure to cross with a balloon or inadequate balloon expansion. In a smaller proportion of cases (20–30%), RA was used safely following dissection and re-entry techniques.31,33,35 Cases requiring RA had similar or slightly lower rates of technical success (77–90% versus 85–89% in nonRA cases). Slow/no reflow has been reported in 17%, while perforation rates vary – tamponade requiring pericardiocentesis occurred in 2.6% of

Calcification in CTOs is common and presents additional challenges during revascularisation of these complex coronary lesions. The presence of calcium predicts lower procedural success rates and a higher risk of complications. Pre-procedural CTCA and intravascular imaging are useful tools to understand the distribution, morphology and severity of calcium. Specialised guidewires and microcatheters, as well as penetration, SIS entry and luminal re-entry techniques, are required to cross calcific CTOs. While the use of each of the balloon-based and atherectomy devices have been reported during CTO PCI, there is limited experience, and some remaining concerns regarding safety and efficacy when used extraplaque.

1. Wilson WM, Walsh SJ, Yan AT, et al. Hybrid approach improves success of chronic total occlusion angioplasty. Heart 2016;102:1486–93. https://doi.org/10.1136/ heartjnl-2015-308891; PMID: 27164918. 2. Morino Y, Abe M, Morimoto T, et al. Predicting successful guidewire crossing through chronic total occlusion of native

While orbital atherectomy has some potential advantages in non-occlusive disease, the location of the ablative crown 6.5 mm proximal to the tip can be a disadvantage in CTO PCI, particularly in balloon uncrossable lesions. Very few cases have been reported. In the PROGRESS substudy, of 3,607 CTO PCI cases, RA was used in 105, orbital atherectomy in eight cases and both were used in four cases.35

Conclusion

coronary lesions within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan) score as a difficulty grading and time assessment tool. JACC Cardiovasc Interv 2011;4:213–21. https://doi.org/10.1016/j.jcin.2010.09.024; PMID: 21349461. 3. Danek BA, Karatasakis A, Karmpaliotis D, et al. Development and validation of a scoring system for predicting

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periprocedural complications during percutaneous coronary interventions of chronic total occlusions: the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS CTO) Complications Score. J Am Heart Assoc 2016;5:e004272. https://doi.org/10.1161/ JAHA.116.004272; PMID: 27729332.

The Impact of Calcium on CTO Management 4. Szijgyarto Z, Rampat R, Werner GS, et al. Derivation and validation of a chronic total coronary occlusion intervention procedural success score from the 20,000-Patient EuroCTO registry: the EuroCTO (CASTLE) score. JACC Cardiovasc Interv 2019;12:335–42. https://doi.org/10.1016/j.jcin.2018.11.020; PMID: 30711551. 5. Maeremans J, Spratt JC, Knaapen P, et al. Towards a contemporary, comprehensive scoring system for determining technical outcomes of hybrid percutaneous chronic total occlusion treatment: the RECHARGE score. Catheter Cardiovasc Interv 2018;91:192–202. https://doi. org/10.1002/ccd.27092; PMID: 28471074. 6. Srivatsa SS, Edwards WD, Boos CM, et al. Histologic correlates of angiographic chronic total coronary artery occlusions: influence of occlusion duration on neovascular channel patterns and intimal plaque composition. J Am Coll Cardiol 1997;29:955–63. https://doi.org/10.1016/S07351097(97)00035-1; PMID: 9120181. 7. Sakakura K, Nakano M, Otsuka F, et al. Comparison of pathology of chronic total occlusion with and without coronary artery bypass graft. Eur Heart J 2014;35:1683–93. https://doi.org/10.1093/eurheartj/eht422; PMID: 24126875. 8. Maurer BJ, Oberman A, Holt JH, et al. Changes in grafted and nongrafted coronary arteries following saphenous vein bypass grafting. Circulation 1974;50:293–300. https://doi. org/10.1161/01.CIR.50.2.293; PMID: 4546527. 9. Pereg D, Fefer P, Samuel M, et al. Native coronary artery patency after coronary artery bypass surgery. JACC Cardiovasc Interv 2014;7:761–7. https://doi.org/10.1016/j. jcin.2014.01.164; PMID 25060019. 10. Guo J, Maehara A, Mintz GS, et al. A virtual histology intravascular ultrasound analysis of coronary chronic total occlusions. Catheter Cardiovasc Interv 2013;81:464–70. https:// doi.org/10.1002/ccd.24356; PMID: 22431273. 11. Karacsonyi J, Karmpaliotis D, Alaswad K, et al. Impact of calcium on chronic total occlusion percutaneous coronary interventions. Am J Cardiol 2017;120:40–6. https://doi. org/10.1016/j.amjcard.2017.03.263; PMID: 28499595. 12. Okamura A, Yamane M, Muto M, et al. Complications during retrograde approach for chronic coronary total occlusion: sub-analysis of Japanese multicenter registry. Catheter Cardiovasc Interv 2016;88:7–14. https://doi.org/10.1002/ ccd.26317; PMID: 26616576. 13. Xenogiannis I, Choi JW, Alaswad K, et al. Outcomes of subintimal plaque modification in chronic total occlusion percutaneous coronary intervention. Catheter Cardiovasc Interv 2020;96:1026–35; https://doi.org/10.1002/ccd.28614; PMID: 31797507. 14. Ito T, Tsuchikane E, Nasu K, et al. Impact of lesion morphology on angiographic and clinical outcomes in patients with chronic total occlusion after recanalization with drug-eluting stents: a multislice computed tomography study. Eur Radiol 2015;25:3084–92. https://doi.org/10.1007/ s00330-015-3706-3; PMID: 25894006. 15. Noguchi T, Miyazaki MS, Morii I, Daikoku S, Goto Y, Nonogi H. Percutaneous transluminal coronary angioplasty of chronic total occlusions. Determinants of primary success

and long-term clinical outcome. Catheter Cardiovasc Interv 2000;49:258–64. https://doi.org/10.1002/(SICI)1522726X(200003)49:3<258::AID-CCD7>3.0.CO;2-L; PMID: 10700054. 16. Mintz GS, Popma JJ, Pichard AD, et al. Patterns of calcification in coronary artery disease. A statistical analysis of intravascular ultrasound and coronary angiography in 1155 lesions. Circulation 1995;91:1959–65; https://doi. org/10.1161/01.CIR.91.7.1959; PMID: 7895353. 17. Kaneda H, Saito S, Shiono T, et al. Sixty-four-slice computed tomography-facilitated percutaneous coronary intervention for chronic total occlusion. Int J Cardiol 2007;115:130–2. https://doi.org/10.1016/j.ijcard.2006.01.045; PMID: 16757046. 18. Rolf A, Werner GS, Schuhbäck A, et al. Preprocedural coronary CT angiography significantly improves success rates of PCI for chronic total occlusion. Int J Cardiovasc Imaging 2013;29:1819–27. https://doi.org/10.1007/s10554-0130258-y; PMID: 23793727. 19. Mollet NR, Hoye A, Lemos PA, et al. Value of preprocedure multislice computed tomographic coronary angiography to predict the outcome of percutaneous recanalization of chronic total occlusions. Am J Cardiol 2005;95:240–3. https://doi.org/10.1016/j.amjcard.2004.09.009; PMID: 15642558. 20. Räber L, Mintz GS, Koskinas KC, et al. Clinical use of intracoronary imaging. Part 1: guidance and optimization of coronary interventions. An expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J 2018;39:3281–300. https://doi. org/10.1093/eurheartj/ehy285; PMID: 29790954. 21. Riley RF, Walsh SJ, Kirtane AJ, et al. Algorithmic solutions to common problems encountered during chronic total occlusion angioplasty: the algorithms within the algorithm. Catheter Cardiovasc Interv 2019;93:286–97. https://doi. org/10.1002/ccd.27987; PMID: 30467958. 22. Fujii K, Carlier SG, Mintz GS, et al. Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: an intravascular ultrasound study. J Am Coll Cardiol 2005;45:995–8. https://doi.org/10.1016/j. accreview.2005.06.046; PMID: 15808753. 23. Doi H, Maehara A, Mintz GS, et al. Impact of postintervention minimal stent area on 9-month follow-up patency of paclitaxel-eluting stents: an integrated intravascular ultrasound analysis from the TAXUS IV, V, and VI and TAXUS ATLAS Workhorse, Long Lesion, and Direct Stent trials. JACC Cardiovasc Interv 2009;2:1269–75. https:// doi.org/10.1016/j.jcin.2009.10.005; PMID: 20129555. 24. Karvouni E, Stankovic G, Albiero R, et al. Cutting balloon angioplasty for treatment of calcified coronary lesions. Catheter Cardiovasc Interv 2001;54:473–81. https://doi. org/10.1002/ccd.1314; PMID: 11747183. 25. Brinton TJ, Ali ZA, Hill JM, et al. Feasibility of shockwave coronary intravascular lithotripsy for the treatment of calcified coronary stenoses. Circulation 2019;139:834–6. https://doi.org/10.1161/CIRCULATIONAHA.118.036531; PMID: 30715944.

26. Ali ZA, Nef H, Escaned J, et al. Safety and effectiveness of coronary intravascular lithotripsy for treatment of severely calcified coronary stenoses: the Disrupt CAD II Study. Circ Cardiovasc Interv 2019;12:e008434. https://doi.org/10.1161/ circinterventions.119.008434; PMID: 31553205. 27. Hill JM, Kereiakes DJ, Shlofmitz RA, et al. Intravascular lithotripsy for treatment of severely calcified coronary artery disease: the Disrupt CAD III study. J Am Coll Cardiol 2020;76:2635–46. https://doi.org/doi:10.1016/j. jacc.2020.09.603; PMID: 33069849. 28. Øksnes A, Cosgrove C, Walsh S, et al. Intravascular lithotripsy for calcium modification in chronic total occlusion percutaneous coronary intervention. J Interv Cardiol 2021:1– 6. https://doi.org/10.1155/2021/9958035; PMID: 34239390. 29. Azzalini L, Bellini B, Montorfano M, Carlino M. Intravascular lithotripsy in chronic total occlusion percutaneous coronary intervention. EuroIntervention 2019;15:e1025–26. https://doi. org/10.4244/EIJ-D-19-00175; PMID: 31012852. 30. Yeoh J, Hill J, Spratt JC. Intravascular lithotripsy assisted chronic total occlusion revascularization with reverse controlled antegrade retrograde tracking. Catheter Cardiovasc Interv 2019;93:1295–7. https://doi.org/10.1002/ ccd.28165; PMID: 30838746. 31. Patel SM, Pokala NR, Menon RV, et al. Prevalence and treatment of “balloon-uncrossable” coronary chronic total occlusions. J Invasive Cardiol 2015;27:78–84; PMID: 25661758. 32. Pagnotta P, Briguori C, Mango R, et al. Rotational atherectomy in resistant chronic total occlusions. Catheter Cardiovasc Interv 2010;76:366–71. https://doi.org/10.1002/ ccd.22504; PMID: 20839349. 33. Azzalini L, Dautov R, Ojeda S, et al. Long-term outcomes of rotational atherectomy for the percutaneous treatment of chronic total occlusions. Catheter Cardiovasc Interv 2017;89:820–8. https://doi.org/10.1002/ccd.26829; PMID: 28029214. 34. Fairley SL, Spratt JC, Rana O, Talwar S, Hanratty C, Walsh S. Adjunctive strategies in the management of resistant, ‘undilatable’ coronary lesions after successfully crossing a CTO with a guidewire. Curr Cardiol Rev 2014;10:145–57. https://doi.org/10.2174/1573403X10666140331124954; PMID: 24694106. 35. Xenogiannis I, Karmpaliotis D, Alaswad K, et al. Usefulness of atherectomy in chronic total occlusion interventions (from the PROGRESS-CTO Registry). Am J Cardiol 2019;123:1422-8. https://doi.org/10.1016/j.amjcard.2019.01.054; PMID: 30798947. 36. Fernandez JP, Hobson AR, McKenzie D, et al. Beyond the balloon: excimer coronary laser atherectomy used alone or in combination with rotational atherectomy in the treatment of chronic total occlusions, non-crossable and nonexpansible coronary lesions. EuroIntervention 2013;9:243–50. https://doi.org/10.4244/EIJV9I2A40; PMID: 23454891. 37. Spratt JC, Hanratty CG, Walsh SJ, Wilson SJ. A guide to mastering antegrade CTO PCI. Optima, 2018.

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Artificial Intelligence

Cardiovascular Imaging and Intervention Through the Lens of Artificial Intelligence Karthik Seetharam , Sirish Shrestha

and Partho P Sengupta

West Virginia University Medicine Heart and Vascular Institute, Morgantown, WV, US

Abstract

Artificial Intelligence (AI) is the simulation of human intelligence in machines so they can perform various actions and execute decision-making. Machine learning (ML), a branch of AI, can analyse information from data and discover novel patterns. AI and ML are rapidly gaining prominence in healthcare as data become increasingly complex. These algorithms can enhance the role of cardiovascular imaging by automating many tasks or calculations, find new patterns or phenotypes in data and provide alternative diagnoses. In interventional cardiology, AI can assist in intraprocedural guidance, intravascular imaging and provide additional information to the operator. AI is slowly expanding its boundaries into interventional cardiology and can fundamentally alter the field. In this review, the authors discuss how AI can enhance the role of cardiovascular imaging and imaging in interventional cardiology.

Keywords

Artificial intelligence, cardiovascular imaging, interventional cardiology, diagnostic tool Disclosure: PPS is a consultant for HeartSciences and Ultromics. All other authors have no conflicts of interest to declare. Received: 7 February 2020 Accepted: 18 June 2021 Citation: Interventional Cardiology 2021;16:e31. DOI: https://doi.org/10.15420/icr.2020.04 Correspondence: Partho P Sengupta, West Virginia University Heart & Vascular Institute, 1 Medical Center Drive, Morgantown, WV 26506, US. E: Partho.Sengupta@wvumedicine.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Artificial intelligence (AI) is a broad term that implies the use of machines to mimic human behaviour and perform various actions with minimal human intervention.1,2 Machine learning (ML), a branch of AI, can analyse information and discover hidden patterns in data.3 The treatment of cardiovascular disease has significantly evolved in interventional cardiology over the last 2 decades.4 Although percutaneous coronary intervention (PCI) is the cornerstone of the catherisation laboratory, many conditions can be treated there, including coronary artery disease (CAD), valvular heart disease, cardiac arrhythmias, pericardial disease, myocardial disease, congenital heart disease and heart failure. With the emergence of transcatheter therapies, the clinical arena of interventional cardiology has greatly expanded. Non-invasive imaging is the critical gatekeeper in the assessment of cardiovascular diseases before cardiovascular intervention.5 AI technologies in imaging are demonstrating their capacity for image interpretation, quality control, diagnostics and improved workflow.6 AI and ML can help discover new variants or phenotypes present within large data in cardiovascular imaging, which can improve our understanding and lead to new therapeutic interventions in CAD.7 They can further aid in interventional cardiology as they can improve clinical decision-making, organise workflow in the catherisation laboratory, facilitate catheter-based intervention through robotic application and predict proper placement to reduce or avoid paravalvular leakage.4,8 Over the last few years, AI has substantially altered the landscape in clinical medicine by providing new insights and opportunities to

improve therapy.6 While AI is evolving in other aspects of human life from self-driving cars to automated voice recognition systems, ML is expanding clinical pathways and opening new frontiers in cardiovascular medicine.9–14 In comparison, the application of ML in interventional cardiology (IC) has been less apparent.13,14 It is evident that AI progress in IC lags behind its counterparts but interest in it is still growing.14 As advances in stent technology and transcatheter aortic valve replacement (TAVR) or transcatheter mitral valve replacement (TMVR) continue, AI will be beneficial.6 In this review, we will discuss how AI will improve the role of cardiovascular imaging and imaging in interventional cardiology.

Potential of Artificial Intelligence in Interventional Cardiology

AI has tremendous capabilities with transformative potential and can perform a wide variety of functions.6 These include pattern recognition, problem-solving, identification of objects and sounds and language comprehension.15,16 In the simplest terms from a clinical standpoint, AI can make data-driven decisions to evaluate disease progression or select the most appropriate treatment.17 Although AI has produced substantial findings in cardiovascular imaging and electrophysiology (Table 1), the role of AI in IC is still in its infancy (Figure 1).4,12 Currently, the practice of AI in IC can be broadly divided into two major disciplines: virtual and physical.14 The virtual branch includes ML algorithms, natural language processing (NLP), cognitive computing and automated clinical decision support systems, whereas the physical branch is mainly restricted to robotic interventional procedures.

AI in Cardiac Imaging and IC Table 1: Recent Examples of Machine Learning in Cardiology Study

ML Algorithm

Field of Cardiology

Study Description

Narula et al. 2016

Supervised learning

Echo

To differentiate between athlete’s heart and hypertrophic cardiomyopathy

Zhang et al. 201831

Deep learning

Echo

To distinguish between different echocardiographic view classes

Sengupta et al. 2016

Supervised learning

Echo

To discern between constrictive pericarditis and restrictive cardiomyopathy

Samad et al. 2019

Deep learning

Echo

To predict survival from echo and EMR information

Betancur et al. 201833

Deep learning

MPI

To assess the prediction of CAD

Betancur et al. 2019

Deep learning

MPI

To evaluate the prediction of CAD in semiupright and supine stress MPI

Arsajani et al. 2013

Deep learning

MPI

To compare accuracy of ML to expert readers for CAD

Arsajani et al. 2015

Supervised learning

MPI

To determine the probability of revascularisation

Haro Alonso et al. 201937

Supervised learning

MPI

To estimate the risk of cardiac death from SPECT and clinical information

Supervised learning

MPI

To predict MACE events from MPI data

van Rosandeal et al. 2018

Deep learning

To compare ML risk scores and current risk scores from CT angiography for CAD

Zreik et al. 2018

Deep learning

To compare fractional flow reserve from CT angiography and invasive coronary angiography

Lessmann et al. 201640

Deep learning

The algorithm created bounding boxes around the heart to determine candidates for coronary artery calcium measurement

Santini et al. 201741

Deep learning

To classify and segment lesions in cardiac CT

Ruijsink et al. 2020

Deep learning

CMR

To compare automatic ventricular measurements with manual findings from CMR

Tan et al. 201744

Deep learning

CMR

To automatically segment the left ventricle in different views from CMR

Cook et al. 2019

AI algorithm

To compare AI with human experts for interpretation of instantaneous wave-free ratio (iFR) pressure-wire pullback traces

Azzalini et al. 201847

Supervised learning

To determine which contrast media was associated with contrast induced kidney injury following PCI

Hernandez-Suraez et al. 201928

Multiple ML algorithms

TAVR

To predict in-hospital mortality following TAVR by an array of ML algorithms

Ghaffar et al. 2019

Unsupervised learning

TAVR

To use ML to determine the 30-day adverse events following TAVR

35 36

Betancur et al. 2018

38 43

AI = artificial intelligence CMR = cardiac MRI; echo = echocardiography; EMR = electronic medical records; IC = interventional cardiology; MACE = major adverse cardiovascular events; PCI = percutaneous coronary intervention; SPECT = single photon emission CT; TAVR = transcatheter aortic valve replacement.

Figure 1: Role of Artificial Intelligence in Cardiovascular lmaging and Interventional Cardiology

Pattern recognition

Big data

Increased prediction

Machine learning

Interventional cardiology

Reduced cost

Automatic diagnosis

Cardiovascular imaging

Improved decisionmaking

Augmented clinical analysis

Types of Machine Learning

Support system

Tailored medical management

ML is a collective term that encompasses a variety of algorithms (Table 2). This includes supervised learning, unsupervised learning and reinforcement learning. The choice of algorithm depends on the indication and purpose of the investigation. Supervised learning uses

specific labels or classes.18 Unsupervised learning analyses a database without labels.10 Semi-supervised learning is a combination of supervised and unsupervised learning.19 Reinforcement learning uses reward criteria similar to human psychology to perform actions.18 Deep learning is one of the most advanced ML algorithms available.20 Supervised and unsupervised learning have demonstrated tremendous potential in cardiovascular imaging, and deep learning (DL) is poised to make the evolutionary leap in ML for cardiovascular imaging.2 It does not require significant training to execute an action.7 It performs significantly better with larger and more complex data sets than other ML algorithms (Figure 2). It requires less domain knowledge to perform various tasks. Among the various algorithms available, DL has the most potential and prowess for prediction.9,11 It is being used in a variety of applications, including voice recognition systems, such as Amazon’s Alexa or Apple’s Siri, and image identification systems.10 DL may process complex information through several layers to process information. It is extracted through each part of the hierarchy and DL can recognise various hidden patterns.9 DL has tremendous capabilities, which are being used in various sectors by the commercial industry and information technology.6

Natural Language Processing

NLP is a branch of AI that comprehends the mechanics of human language.14 This method can be applied to electronic medical records (EMRs) for large-scale text analysis and data extraction. Similar to ML algorithms, it may be used to identify complications and postoperative

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AI in Cardiac Imaging and IC Table 2: Types of Machine Learning Types of Machine Learning

Description

Examples

Supervised learning

The data contains labels and outcomes

This includes logistic regression, Bayesian networks, random forests, ridge regression, elastic net regression, least absolute shrinkage and selection operator (LASSO) regression, and artificial neural networks10,18

Unsupervised learning

It detects vital relationships and similarities in unlabeled datasets

It encompasses of hierarchical clustering, k-means clustering, and principal-component analysis10,18

Semi-supervised learning

Hybrid of supervised and unsupervised learning.

It contains a combination of labelled and unlabelled outcomes and classes, used in image and speech recognition10,18

Reinforcement learning

Based on behavioural psychology, uses reward function

Uses certain reward criteria, it is seen in medical imaging, analytics, disease screening, and prescription selection10,18

events to streamline clinical workflows.21,22 Furthermore, NLP can be used to analyse data from heterogeneous sources with various formats, which can be advantageous to IC. It has been applied in risk scoring, adverse drug event identification or patient selection for cardiac resynchronisation therapy, to name a few.23–25

Computer Vision

Computer vision uses image processing and ML algorithms to detect features or pattern recognition in digital or video imaging.18,26 Computer vision algorithms coupled with deep learning can provide an automated interpretation of complex radiological images to assist or train cardiologists.27 This may play an important role in IC for identifying potential complications in the placement of valves and structural defects.14,28 Currently, there are troves of IC data that can be analysed by ML algorithms to predict adverse events.

Clinical Decision Support System

Clinical decision support systems use information in EMRs and present summaries and notification that are relevant to healthcare providers in implementing evidence-based clinical practice. They may provide information regarding risk factors, drug interaction information or information relevant to patients undergoing catheterisation. Because it relies on EMRs, NLP could be imperative to decision support systems. However, ML could also be used to interpret images for treatment approaches and aid in medical management.14

Role of AI in Echocardiography

Echocardiography is the primary image modality in cardiology and plays a central role in most diagnostic pathways for several pathological entities.19 In several recent studies, ML algorithms have shown innovative applications in findings using echocardiographic parameters.11 Although echocardiography is widely used, its results can be heterogeneous.29 These variables can affect management and outcomes for the interventionist. Machine learning can produce rapid and consistent findings, which can help budding interventionists in clinical decision-making.29 In our own experience, we have harnessed the capabilities of AI to identify differences between hypertrophic cardiomyopathy and athlete’s heart, and applied a supervised learning algorithm to differentiate between restrictive cardiomyopathy and constrictive pericarditis.5,30 Similarly, Zhang et al. used a convolutional neural network (CNN), a DL algorithm, for automated image interpretation.31 The ML algorithm was trained to identify 23 viewpoints and segmentation of cardiac chamber

Figure 2: Evolution of Artificial Intelligence in Cardiovascular Imaging

Supervised

Unsupervised

Semi-supervised

Reinforcement

Artificial intelligence

Machine learning Deep learning

across five common views. Impressively, the algorithm was successful in identifying views (96% for parasternal long axis) and enabled the segmentation of cardiac chambers. Samad et al. used a random forest ML algorithm to predict survival by using echocardiography measurements and electronic medical information in 171,510 patients.32 The random forest models demonstrated superior prediction accuracy (all AUC [area under the curve] >0.82) over common clinical risk scores (AUC 0.69–0.79). Also, the ML models outperformed logistic regression models (p<0.001 and all survival durations).

Role of AI in Nuclear Medicine

Myocardial perfusion imaging (MPI) has an important role in nuclear medicine and provides vital information in CAD.9 Single-photon emission CT (SPECT) enables physicians to identify perfusion defects. MPI is a non-invasive modality that has a paramount role in risk stratification for CAD.9 With ML algorithms, it can integrate clinical information and a large number of parameters to predict CAD, revascularisation and major adverse cardiovascular events (MACE).16 These aspects can be particularly useful for interventionists as they can assist in clinical management and patient selection for high-risk procedures. Betancur et al. assessed the prediction of obstructive coronary artery disease (CAD) using myocardial perfusion imaging (MPI) by a DL algorithm.33 The ML algorithm demonstrated a higher area under the receiver-operating curve than total perfusion deficit (TPD) for CAD prediction (per patient 0.80 versus 0.78; per vessel 0.76 versus 0.73; p<0.01). Recently, Betancur et al. also assessed a deep learning algorithm for the prediction of obstructive CAD with a combination of semi-upright

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AI in Cardiac Imaging and IC and supine stress MPI in comparison with TPD.34 Similarly, the area under the receiver-operating curve for prediction of disease per patient and per vessel by the ML algorithm was better (per patient, 0.81 versus 0.78; per vessel 0.77 versus 0.73, p<0.001).34 Arsajani evaluated the combination of clinical and imaging data to predict CAD using SPECT.35 The receiveroperating curve for the ML method was better than TPD and two readers with considerable significance (p<0.001). Arsajani et al. examined clinical and imaging data to determine the probability of revascularisation in 713 patients with suspected CAD through a LogitBoost supervised learning algorithm.36 The specificity of the ML algorithm was better than both expert readers (p<0.05) and similar to total perfusion deficit (p<0.05). In addition, the receiver-operating curve for the ML architecture (0.81 ± 0.02) was similar to reader 1 (0.81 ± 0.02), but better than reader 2 (0.72 ± 0.02; p<0.01) and the standalone measure of perfusion (0.77 ± 0.02; p<0.01). Alonso et al. used a supervised ML algorithm to estimate the risk of cardiac death, derived from an amalgamation of adenosine myocardial perfusion SPECT with clinical information in 8,321 patients and 551 cases of cardiac death.37 The logistic regression was outperformed by the ML algorithm (AUC 0.76; 14 features). It evidently showed superior accuracy (AUC 0.83; p<0.0001; 49 features). Nonetheless, the least absolute shrinkage and selection operator (LASSO) model required the least number of features (AUC 0.77; p=0.045; six features). Betancur et al. explored the predictive value of patient information with SPECT MPI to predict MACE through a LogitBoost supervised learning ML algorithm in 2,619 patients.38 At around 3 years’ follow-up, 239 patients had experienced MACE. Interestingly, the ML combined achieved superior MACE prediction than ML imaging (AUC 0.81 versus 0.78; p<0.01). The ML also had higher MACE predictive accuracy when compared with an expert reader, automated stress total perfusion deficit and automated ischaemic perfusion deficit (AUC 0.81 versus 0.65 versus 0.73 versus 0.71; p<0.01 for all).

Role of AI in Cardiac CT

CT is a non-invasive approach for the identification of obstructive CAD. CT enables the depiction of the underlying coronary anatomy to visualise plaques or stenosis in the coronary artery tree.39 From an interventionist point of view, cardiac CT plays an important role in appropriate selection for PCI. Among all non-invasive modalities, CT angiography closely mirrors invasive angiography. ML algorithms can greatly augment the possibilities of cardiac CT. Lessmann et al. used a convolutional neural network (CNN), a deep learning algorithm, to create a bounding box around the heart that corresponds to certain Hounsfield units.40 They investigated the potential of an automated coronary calcium system that was able/would be to screen patients for high-risk cardiovascular events. Santini et al. explored the role of a CNN algorithm in classifying and segmenting lesions in cardiac CT imaging.41 After proper training of the CNN algorithm with various CT volumes, they were able to demonstrate a Pearson correlation measuring 0.983. Zreik et al. used a CNN algorithm to automatically calculate the fractional flow reserve (FFR) from coronary CT angiography.42 Surprisingly, there was good agreement between the ML-derived values and invasively measured one, with the AUC being 0.74. Rosendael et al. examined the role of a boost ensemble algorithm to compare ML-derived scores and current risk scores in CT angiography for CAD evaluation.43 The events

expressed by the AUC was superior by the ML algorithm in reference to conventional scores (0.771 versus 0.685 to 0.701; p<0.001).

Role of AI in Cardiac MRI

Cardiovascular magnetic resonance (CMR) imaging has emerged as a robust diagnostic modality for assessing a variety of clinical conditions in cardiology. Of the various non-invasive approaches, it is the only option that permits tissue characterisation. CMR can be used by the interventionist to plan appropriate management for patients. During procedures, CMR imaging can be used to guide complex procedures because of the minimal risk of radiation. Tan et al. assessed the role of the CNN algorithm for automatic segmentation of the left ventricle in short-axis slices in publicly available database.44 Interestingly, the ML algorithm achieved a Jaccard index of 0.77 for the left ventricle segmentation challenge dataset and obtained a continuously ranked probability score of 0.0124 for the Kaggle Second Annual Data Science Bowl. Similarly, Ruijinsk et al. evaluated the role of the CNN framework for automated ventricular function assessment from cardiac CMR.45 The findings corroborated highly with manual analysis for left ventricular and right ventricular volumes (all r >0.95), strain (circumferential r = 0.89; longitudinal r >0.89) and ejection rates (all r ≥0.93).

Can AI-integrated Cardiovascular Imaging Facilitate Interventional Therapies?

Using the vast troves of cardiovascular imaging enables the possibilities of data-driven phenotypic differentiation.46 This has particular relevance in the field of IC and transcatheter therapies for enabling individualised therapies.5 Algorithms integrating ML and cardiovascular imaging can help generate patient-specific risk scores, which can yield diagnostic significance in procedural planning.14 Furthermore, ML may play a paramount role in automating cardiovascular imaging workflow for referral of patients to cardiac catherisation laboratory by facilitating faster reading, interpretation and diagnosis.5,14 In addition, ML algorithms may help predict outcomes such as mortality or complications following interventional therapies.

Role of AI in Percutaneous Coronary Intervention and Transcatheter Aortic Valve Replacement

Although the potential of AI has not been fully harnessed in PCI, a few studies provide a glimpse of AI in the near future.14 One aspect of considerable variability in interpretation is physiologically guided coronary revascularisation.8 The consistency of results can be improved with AI. Cook et al. compared an AI algorithm with 15 human experts for interpretation of 1,008 instantaneous wave-free ratio (iFR) pressure-wire pullback traces.13 In addition, a heart team interpretation was determined by a consensus of individual opinions. The median human expert had an 89.3% agreement with heart team response, while it was 89.4% with AI (p<0.01 for non-inferiority) for PCI haemodynamic appropriateness. Within the 372 cases evaluated for haemodynamic appropriateness, the AI framework had 89.7% agreement while the median human expert was 88.8% in agreement with the heart team response (p<0.01 for non-inferiority). Cook et al. confirmed that the AI algorithm was not inferior to the expert decision making for determining the appropriateness and strategy of PCI.13 Azzalini et al. used a generalised boost regression to determine which contrast media among five types was associated with contrast-induced

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AI in Cardiac Imaging and IC kidney injury following PCI in 2,648 patients.47 In a risk-adjusted analysis, Azzalini found no particular contrast type was associated with contrastinduced kidney injury when compared to iodixanol. Currently, few centres have explored the role of AI in TAVR. HernandezSuarez used ML algorithms to predict in-hospital mortality after TAVR in 10,883 patients using data derived from the national inpatient sample.28 The AUC for the ML algorithm was greater than 0.80. They were able to show ML could generate risk models capable of predicting in-hospital mortality. Ghaffar explored the role of topological data analysis (TDA) network to predict 30-day complications and mortality following TAVR in 228 patients.48 Four clusters were identified. Cluster A had more frequent vascular intervention (p<0.016), while clusters B and D had a higher number of procedures before TAVR (p<0.04). Clucert C underwent TAVR. Major adverse complications were seen in the first week of complications in clusters C and D (p<0.05). Interestingly, there was no difference in the Society of Thoracic Surgeon’s risk scores between either cluster.

Role of AI in Robotics

Interest is surging in robotic technology for IC because it can deliver precise, efficient clinical care.4 Robotic technology has the capability to reduce variability in procedure time, accurately assess lesion length and decrease the number of stents used.4 Robots can be used in training young interventionists. Though robotics has the potential to open new doors in IC, it is not without flaws.14 There are fundamental differences between interventionists and their accompanying robotic assistants. These systems do not recognise the underlying anatomy or understand the intentions of the operator. ML algorithms, computer vision and image interpretation can truly help in this process by bridging the gap between man and machine.26 They can enhance the underlying technology to possibly enable some degree of automation and possible decision-making.14 Future robotic systems may be able to assess previous procedures and provide feedback to interventional cardiologists.

Our Evolving Views on AI in Cardiovascular Imaging and Interventional Cardiology

Although AI has clearly caused paradigm shifts in cardiovascular imaging, the application of AI for IC is still in its early stages.14 AI is poised to create revolutionary progress in IC in years to come (Figure 3). AI offers the possibility of detecting patients with high-risk profiles and gauge treatment effects according to various factors. In the catherisation laboratory, AI can assist in procedural guidance for angiography, intravascular imaging and provide any form of additional support to the operator during the procedure.4 Shortly, AI could provide patient-specific, vessel-specific or even lesionspecific revascularisation strategies.8 Based on outcome data arising from national and international registries, this could be tapped by AI to create treatment strategies to improve short- and long-term outcomes. 1. Hamet P, Tremblay J. Artificial intelligence in medicine. Metabolism 2017;69(Suppl):S36–40. https://doi.org/10.1016/j. metabol.2017.01.011; PMID: 28126242. 2. Seetharam K, Brito D, Farjo PD, Sengupta PP. The role of artificial intelligence in cardiovascular imaging: state of the art review. Front Cardiovasc Med 2020;7:618849. https://doi. org/10.3389/fcvm.2020.618849; PMID: 33426010. 3. Seetharam K, Sengupta PP, Bianco CM. Cardiac mechanics

Figure 3: Future of Artificial Intelligence in Interventional Cardiology and the Catheterisation Laboratory

Robotic assistance in cath laboratory

Augmented reality

Current cath lab

Clinical decision support systematic

Voice-assisted control system

Though AI may appear revolutionary, it is not without limitations.20 Several risks are associated with AI. Although AI and DL are extremely capable of extrapolating patterns from data, they can misinterpret information.49 This can lead to an inaccurate classification of information. Some changes can be minuscule and not noticed by human perception.49 This can perplex the best operating ML algorithms and can have severe ramifications in healthcare. There is a possibility of misinterpreting information as well. Cardiologists must be cognisant of the risks of AI and be educated on its strengths and weakness.20 They must not blindly accept the actions of AI. By being aware of the risks, we can fully tap the potential of AI in IC. Many echocardiographers have played a key role in the development of AI and ML algorithms in cardiovascular imaging.12 Similarly, interventionists must play an active role in the genesis and propagation of AI in IC.8 Interventionists can provide clinically relevant information to engineers regarding the nature of IC data. Engineers can use this data to create practical solutions in the field of IC. Such algorithms could benefit the interventionist, streamline the workflow and help to minimise error. Collaboration between interventionists and engineers needs to occur at national and international levels for AI to truly flourish in IC.

Conclusion

AI is playing a paramount role in diagnostic imaging by integrating vast amounts of information. Similarly, AI is beginning to take root in IC. It can expand options for procedural guidance, intraprocedural analysis, robotics and clinical judgement. As interventionists learn to adopt AI in clinical practice, it will revolutionise IC treatment strategies. There may be some initial hurdles, and difficulties are inevitable in the path to progress. The trinity of human, machine and patient will be the focal point of IC along with imaging in years to come.

in heart failure with preserved ejection fraction. Echocardiography 2020;37:1936–43. https://doi.org/10.1111/ echo.14764, PMID: 32594605. 4. Kerneis M, Nafee T, Yee MK, et al. Most promising therapies in interventional cardiology. Curr Cardiol Rep 2019;21:26. https://doi.org/10.1007/s11886-019-1108-x; PMID: 30868280. 5. Narula S, Shameer K, Salem Omar AM, et al. Machinelearning algorithms to automate morphological and

functional assessments in 2D echocardiography. J Am Coll Cardiol 2016;68:2287–95. https://doi.org/10.1016/j. jacc.2016.08.062; PMID: 27884247. 6. Dey D, Slomka PJ, Leeson P, et al. Artificial intelligence in cardiovascular imaging: JACC state-of-the-art review. J Am Coll Cardiol 2019;73:1317–35. https://doi.org/10.1016/j. jacc.2018.12.054; PMID: 30898208. 7. Seetharam K, Raina S, Sengupta PP. The role of artificial

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cardiac death after adenosine myocardial perfusion SPECT based on machine learning. J Nucl Cardiol 2019;26:1746–54. https://doi.org/10.1007/s12350-018-1250-7; PMID: 29542015. 38. Betancur J, Otaki Y, Motwani M, et al. Prognostic value of combined clinical and myocardial perfusion imaging data using machine learning. JACC Cardiovasc Imaging 2018;11:1000–9. https://doi.org/10.1016/j.jcmg.2017.07.024; PMID: 29055639. 39. Karlo CA, Leschka S, Stolzmann P, et al. A systematic approach for analysis, interpretation, and reporting of coronary CTA studies. Insights Imaging 2012;3:215–28. https://doi.org/10.1007/s13244-012-0167-y; PMID: 22696084. 40. Lessmann N, Išgum I, Setio AA, et al. Deep convolutional neural networks for automatic coronary calcium scoring in a screening study with low-dose chest CT. Presented at Medical Imaging: Computer-Aided Diagnosis 2016, San Diego, California. 27 February–3 March 2016. https://doi. org/10.1117/12.2216978. 41. Santini G, Della Latta D, Martini N, et al. An automatic deep learning approach for coronary artery calcium segmentation. In: Eskola H, Väisänen O, Viik J, Hyttinen J, eds. EMBEC & NBC 2017. EMBEC 2017, NBC 2017. IFMBE Proceedings 2017;65. Singapore: Springer. https://doi. org/10.1007/978-981-10-5122-7_94. 42. Zreik M, Lessmann N, van Hamersvelt RW, et al. Deep learning analysis of the myocardium in coronary CT angiography for identification of patients with functionally significant coronary artery stenosis. Med Image Anal 2018;44:72–85. https://doi.org/10.1016/j.media.2017.11.008; PMID: 29197253. 43. van Rosendael AR, Maliakal G, Kolli KK, et al. Maximization of the usage of coronary CTA derived plaque information using a machine learning based algorithm to improve risk stratification; insights from the CONFIRM registry. J Cardiovasc Comput Tomogr 2018;12:204–9. https://doi. org/10.1016/j.jcct.2018.04.011; PMID: 29753765. 44. Tan LK, Liew YM, Lim E, McLaughlin RA. Convolutional neural network regression for short-axis left ventricle segmentation in cardiac cine MR sequences. Med Image Anal 2017;39:78–86. https://doi.org/10.1016/j.media.2017.04.002; PMID: 28437634. 45. Ruijsink B, Puyol-Anton E, Oksuz I, et al. Fully automated, quality-controlled cardiac analysis from CMR: validation and large-scale application to characterize cardiac function. JACC Cardiovasc Imaging 2020;13:684–95. https://doi. org/10.1016/j.jcmg.2019.05.030; PMID: 31326477. 46. Wang Y, Goh W, Wong L, Montana G. Random forests on Hadoop for genome-wide association studies of multivariate neuroimaging phenotypes. BMC Bioinformatics 2013;14 (Suppl 16):S6 https://doi.org/10.1186/1471-2105-14-s16-s6; PMID: 24564704. 47. Azzalini L, Vilca LM, Lombardo F, et al. Incidence of contrast-induced acute kidney injury in a large cohort of allcomers undergoing percutaneous coronary intervention: comparison of five contrast media. Int J Cardiol 2018;273:69– 73 https://doi.org/10.1016/j.ijcard.2018.08.097; PMID: 30196995. 48. Ghaffar YA, Shaukat F, Desai A, et al. Machine learning using similarity analysis improves risk stratification beyond surgical risk scores in patients undergoing transcatheter aortic valve replacement. J Am Coll Cardiol 2019;73(9 Suppl 1):1371. https://doi.org/10.1016/S0735-1097(19)31978-3. 49. Heaven D. Why deep-learning AIs are so easy to fool. Nature 2019;574:163–6 https://doi.org/10.1038/d41586-019-03013-5; PMID: 31597977.

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Coronary

What an Interventionalist Needs to Know About INOCA Daniel Tze Yee Ang

1,2

and Colin Berry

1,2

1. University of Glasgow, Glasgow, UK; 2. Golden Jubilee National Hospital, Clydebank, UK

Abstract

Ischaemia with non-obstructed coronary artery disease (INOCA) remains a diagnostic and therapeutic challenge. An anatomical investigationbased approach to ischaemic heart disease fails to account for disorders of vasomotion. The main INOCA endotypes are microvascular angina, vasospastic angina, mixed (both) or non-cardiac symptoms. The interventional diagnostic procedure (IDP) enables differentiation between clinical endotypes, with linked stratified medical therapy leading to a reduced symptom burden and a better quality of life. Interventionists are therefore well placed to make a positive impact with more personalised care. Despite adjunctive tests of coronary function being supported by contemporary guidelines, IDP use in daily practice remains limited. More widespread adoption should be encouraged. This article reviews a stratified approach to INOCA, describes a streamlined approach to the IDP and highlights some practical and safety considerations.

Keywords

Ischaemia with no obstructive coronary artery disease, ischaemic heart disease, coronary, angina, coronary microvascular dysfunction, vasospastic angina, interventional diagnostic procedure Disclosure: DA and CB are employed by the University of Glasgow, which holds consultancy and research agreements with companies that have commercial interests in the diagnosis and management of angina, including Abbott Vascular, AstraZeneca, Boehringer Ingelheim, GSK, Heartflow, Menarini Pharmaceuticals, Neovasc, Siemens Healthcare and Valo Health. The authors received no support from any of these organisations for the submitted work. Acknowledgments: The authors thank the patients and colleagues who have contributed to the body of knowledge cited in this article. Received: 30 May 2021 Accepted: 23 September 2021 Citation: Interventional Cardiology 2021;16:e32. DOI: https://doi.org/10.15420/icr.2021.16 Correspondence: Daniel Tze Yee Ang, Research Office, Coronary Care Unit, Golden Jubilee National Hospital, Agamemnon St, Clydebank G81 4DY, UK. E: danielang.ty@doctors.org.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The classic cause of ischaemic heart disease is epicardial coronary atherosclerosis, but disorders of coronary vasomotion are being increasingly identified.1–4 Anatomical imaging with CT coronary angiography (CTCA) is the first-line test for patients with known or suspected angina and no prior history of coronary artery disease (CAD).5 Anatomical imaging is useful to clarify the presence and extent of coronary atherosclerosis, but does not evaluate microvascular function or coronary artery spasm. This presents a diagnostic gap for patients with ischaemia with non-obstructed coronary artery disease (INOCA). The strengths of invasive angiography are its high sensitivity for revealing coronary atherosclerosis, providing haemodynamic measurements and the option of following on with percutaneous coronary intervention (PCI). Its limitations are, first, that its spatial resolution of approximately 0.3 mm is insensitive in visualising resistance arterioles that help to modulate myocardial blood flow.2 Second, angiography does not directly assess vascular function. Despite adjunctive tests of coronary function now being recommended (class IIa) by contemporary guidelines, its uptake in daily practice remains limited.4 Up to 50% of patients with known or suspected angina have INOCA.3 Of these, 80% are found to have microvascular and vasospastic angina when studied using specific tests.3,6,7 These conditions are associated with an impaired quality of life, as well as greater morbidity and health resource utilisation.8,9,10 Dismissing these patients would be doing them a disservice.

Interventional cardiologists are uniquely placed in the care pathway to offer gold-standard assessment of the coronary circulation via the interventional diagnostic procedure (IDP). While disorders of coronary function may coexist in patients with epicardial stenosis, diagnostic testing remains limited in the presence of obstructive CAD. This review focuses on the diagnosis of INOCA, describes a streamlined approach to the IDP, and highlights some practical and safety considerations.

Importance of Diagnosis

Illness perception tends to be more threatening in patients with diagnostic uncertainty, which in turn leads to disability and absence from work.11 A conclusive diagnosis can be therapeutic, encouraging compliance with medication and lifestyle interventions. The CorMicA study demonstrated that an IDP with linked stratified medical therapy improved symptom burden, quality of life, treatment satisfaction and illness perception at 6 and 12 months.6,12 Invasive coronary angiography could therefore be considered incomplete without assessment of coronary vascular function.

Alternative Approaches

Some clinicians propose that ex juvantibus criteria for the management of these patients could convey the same benefits without an IDP, by instituting a therapeutic trial of vasomotor-specific antianginals in all patients. The arguments for this approach include a shorter procedural duration and reduced upfront cost from diagnostic guidewires, adenosine and acetylcholine.

INOCA for the Interventionalist Table 1: INOCA Diagnosis Clinical Endotype

Diagnostic Criteria

Evidence

Microvascular angina

1. Symptoms of myocardial ischaemia

Effort or rest angina/angina-equivalent, including dyspnoea

2. Absence of obstructive coronary artery disease (<50% stenosis or FFR >0.80)

CTCA or invasive coronary angiography ± FFR

3. Objective evidence of myocardial ischaemia

Ischaemic ECG during episode of chest pain and/or abnormal functional tests (e.g. myocardial perfusion or regional wall motion abnormality).

4. Evidence of impaired coronary microvascular function CFR ≤2.0 (2.1–2.5 grey-zone result), IMR ≥25, HMR ≥2.5 mmHg/cm/s, and/or microvascular spasm (TIMI flow ≤2) during vasoreactivity testing Vasospastic angina

1. ≥90% epicardial vasoconstriction

≥90% reduction in coronary luminal diameter versus baseline during vasoreactivity testing

2. Reproduction of usual anginal symptoms

Angina/ angina-equivalent symptoms including chest discomfort and dyspnoea

3. Ischaemic ECG changes

ST-segment deviation ≥0.1 mV or new negative U waves

Mixed (microvascular and vasospastic)

Overlap condition meeting criteria for both microvascular angina and vasospastic angina

Evidence of microvascular dysfunction in the presence of significant (≥90%) epicardial vasoconstriction

Non-cardiac symptoms

Unobstructed coronary arteries with normal coronary function test results

<50% stenosis or FFR >0.80, with normal CFR, IMR/HMR and vasoreactivity testing

Coronary Vasomotor Disorders International Study Group Diagnostic Criteria for INOCA. CFR = coronary flow reserve; CTCA = CT coronary angiography; FFR = fractional flow reserve; HMR = hyperaemic microvascular resistance; IMR = index of microcirculatory resistance; TIMI = thrombolysis in MI. Source: Ong et al. 2018.14 Adapted with permission from Elsevier.

Stratified Medicine

Stratified medicine is the identification of key subgroups within a heterogeneous population of patients, each with differing disease mechanisms and/or responses to treatment. Mechanistically linked treatments should be prescribed based on clinical endotypes, as determined from results of the IDP. Unnecessary medication should be discontinued, minimising polypharmacy and its possible side effects. This concept aligns with precision medicine – offering the ‘right treatment for the right patient at the right time’.13 Stratification can improve mechanistic understanding of disease to enable development of biomarkers and identify new disease-specific targets for treatment.13

to inflammation, inward remodelling of the vascular wall or interstitial matrix and/or capillary rarefaction.16 Remodelled arterioles have also demonstrated hypersensitivity to vasoconstricting stimuli.17

Epicardial Vasospastic Angina

Focal epicardial spasm was first described by Prinzmetal et al. in 1959 as ‘variant angina’.18 The defining feature is hyper-reactivity to vasoconstrictor stimuli. This includes both spontaneous spasm and episodes during provocation testing. It may exhibit a circadian pattern and be precipitated by stress or hyperventilation. Vasospastic angina (VSA) typically occurs at rest but may also be induced by exertion in a minority of people.

Ultimately, many of these patients are significantly affected by their symptoms, such that they may be willing to undergo invasive angiography with its small risk of life-threatening complications. We owe it to them to inform them about the risks and benefits and offer opportunity for further assessment.

Mixed Microvascular and Vasospastic Angina

Defining INOCA by Clinical Endotypes

When coronary arteries are unobstructed and coronary function results are normal, alternative aetiologies for symptoms should be considered.

Physiological coronary vascular function reflects a balance between vascular tone, vasodilator reserve and resistance. Vascular function may vary between coronary artery territories. Disorders cause a relative supply-demand mismatch of blood flow relative to requirements, resulting in ischaemia. INOCA is considered after obstructive epicardial disease has been excluded via standard angiography, with or without measurement of non-hyperaemic pressure ratios and/or fractional flow reserve (FFR). The main INOCA endotypes to consider are described below. The Coronary Vasomotor Disorders International Study Group (COVADIS) has published standardised definitions to aid clinical diagnosis (Table 1).14

Microvascular Angina

Microvascular angina (MVA) may involve one or more distinct mechanisms. This concept has also been described in heart failure with preserved ejection fraction.15 MVA is caused by microcirculatory disorders that may be functional, structural or both. Functional disorders impair coronary arteriolar vasodilation or vasoconstriction. Structural disorders relate

VSA may coexist with microvascular disorders and/or structural epicardial disease. There is evidence that patients with mixed MVA/VSA have worse overall quality of life.19

Non-Cardiac Symptoms

Functional Coronary Angiography and the Interventional Diagnostic Procedure

Functional coronary angiography integrates anatomical imaging with functional tests. The IDP increases the diagnostic yield and differentiative power of invasive angiography among patients with unobstructed epicardial coronaries. The additional information provided reduces diagnostic uncertainty and related variations in treatment.6 The assessment of INOCA comprises two main components: diagnostic, guidewire-based assessment comparing flow at rest versus during hyperaemia; and pharmacological provocation testing for epicardial and/ or microvascular vasoconstriction. There is some debate regarding which test should be performed first. The authors advocate performing guidewire/adenosine studies first because of the risk of profound vasoconstriction during provocation testing, which can in turn elevate sympathetic drive and disrupt resting haemodynamic

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INOCA for the Interventionalist physiology. This accepts the small risk of incomplete nitrate metabolism before vasoreactivity testing.

Figure 1: Interventional Diagnostic Procedure Workflow Summary of the IDP with practical considerations at each stage

Current diagnostic guidewires use either a pressure/temperature sensor for thermodilution or a Doppler/pressure sensor. Thermodilution-based wires are safe and straightforward to use.6 Doppler/pressure wires may have higher accuracy and better correlation with non-invasive testing results, but at the expense of wire manoeuvrability.20 This review focuses on thermodilution-based guidewires and acetylcholine provocation testing. A streamlined workflow with its practical considerations is summarised in Figure 1.

Invasive coronary angiography + left ventricular end-diastolic pressure • Radial approach • No vasoreactive medication ≥24 h, including in radial cocktail • Short-acting nitrate (e.g. glyceryl trinitrate) preferred during procedure • Choose projections showing length of vessel without foreshortening or overlap • Exclude significant epicardial coronary stenosis

3 ml bolus 18° saline

In practice, the IDP takes approximately 20 minutes, similar to singlevessel PCI.6 However, the benefits of complete diagnostic assessment should be acknowledged, including the reduced need for repeat referrals in the future.

General Considerations

Patient comfort and safety are paramount. A radial approach is recommended as per contemporary guidelines.4 An anxiolytic sedative facilitates a favourable patient experience but may, theoretically, reduce the propensity for inducing coronary spasm during acetylcholine provocative testing. All vasoactive medication should be withheld >24 hours beforehand, including abstinence from caffeine. This reduces the risk of false-negative results during vasoreactivity testing. Calcium channel blockers and long-acting nitrates should be avoided in the radial cocktail. Short-acting nitrates such as glyceryl trinitrate (which has a halflife of ~2 minutes) are preferred. Rapidly metabolised nitrates minimise the risk of false-negative results during vasoreactivity testing.21 Measuring left ventricular end-diastolic pressure is recommended as elevated pressures might suggest alternative explanations for symptoms (e.g. decompensated heart failure), which may themselves be associated with microvascular dysfunction.

Diagnostic Guidewire Assessment

Resting thermodilution indices should be obtained in all patients undergoing FFR studies. This allows the option of completing hyperaemic indices during a single adenosine infusion after the FFR result is acquired. A bolus of intracoronary short-acting nitrate at the start mitigates any confounding epicardial spasm at rest. The guiding catheter is flushed with normal saline to avoid pressure-damping from contrast or blood. Allow 30 seconds for resting conditions to return before performing pressure wire equalisation. Meticulous initial set-up reduces the risk of pressure wire signal drift downstream. The choice of guiding catheter should be personalised, taking account of the patient’s stature. A 6 Fr or 5 Fr guiding catheter represents an ideal balance between size, support and patient tolerability. ‘Balloon tracking’ or, alternatively, a ‘mother-and-child’ technique of advancing a 5 Fr diagnostic pigtail catheter inside a 6 Fr guide catheter can help overcome issues with radial spasm and shearing injury during catheter advancement. The benefits of good catheter support are threefold: first, it reduces variation in the volume delivered from each saline bolus; second, less in-and-out recoil of the catheter during rapid bolus injections reduces the risk of vessel injury; and third, reduced catheter movement stabilises the diagnostic guidewire position within the vessel, thereby reducing variability in transit times. Heparin (50–70 U/kg) should be administered to achieve an activated clotting time (ACT) of approximately 250 seconds before coronary

0.014" diagnostic wire

Distal third of vessel IDP step 1: diagnostic guidewire study + adenosine • 6 Fr guide – ‘mother-and-child’ or ‘balloon tracking’ to facilitate catheter advancement if needed • Short-acting intracoronary nitrates to negate any epicardial spasm at rest • Flush guide and await return of resting conditions before equalisation • Diagnostic guidewire to distal third of target vessel (left anterior descending artery by default) • Standard coronary wire acting as ‘buddy wire’ can help advancement of diagnostic wire • Flush guide catheter before acquiring resting thermodilution transit times using a 3 ml syringe for saline boluses. Replace any outlier results for accurate CFR/IMR • Commence IV adenosine and repeat transit times after stable hyperaemia is confirmed

Acetylcholine infusion

Monitor vitals, symptoms, ECG, repeat angiogram Vasoconstriction

IDP step 2: vasoreactivity provocation testing • Choice between infusion via standard guiding catheter versus dedicated microcatheter • Incremental acetylcholine challenge: infusions of 10−6, 10−5 and 10−4 at 1 ml/min for 2 mins. Finally, bolus of 100 µg over 20 secs • Monitor patient for change in vitals, heart rhythm and/or symptoms during infusions • Purge catheter after each infusion to avoid bolus of acetylcholine with next injection • Repeat angiogram after each infusion and compare to baseline. Assess for change in luminal diameter (>90% reduction = vasospastic angina) or drop in TIMI flow (microvascular spasm) • Spasm should be relieved immediately with intracoronary nitrates • Bradycardia and heart block are usually self limiting, and can be mitigated with patient coughing manoeuvres. Chemical and electrical pacing are rarely necessary

CFR = coronary flow reserve; IDP = interventional diagnostic procedure; IMR = index of microvascular resistance; TIMI = thrombolysis in MI.

instrumentation. The left anterior descending artery is the default artery of choice because of its subtended myocardial mass. The pressure wire should be advanced to the distal third of the target vessel. If advancing the diagnostic guidewire is difficult, pathfinding with a standard coronary guidewire that acts as a ‘buddy wire’ can be helpful. This is particularly pertinent if using a combination Doppler/pressure wire. With the diagnostic guidewire positioned, the guiding catheter is again flushed to expel any saline warmed by the patient’s body temperature. After resting haemodynamic conditions have returned, resting transit times are acquired with brisk 3 ml injections of room-temperature saline, administered via a coaxial guiding catheter to avoid hydro-trauma. In large left-dominant circulations, 5 ml injections may be required. The manifold should be immediately switched back to live pressure recording after each injection to allow simultaneous measurement of aortic and distal coronary pressures. Movement of the manifold should be minimised to

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INOCA for the Interventionalist Figure 2: Flowchart for Diagnosis of Different INOCA Endotypes, with Typical Examples

IDP Step 1

Diagnostic guidewire study Thermodilution transit times at rest and at maximal hyperaemia (adenosine)

Abnormal IMR ≥25 and/or CFR <2.0 (Grey-zone CFR 2.0–2.5)

Normal IMR <25 and/or CFR >2.5 (Grey-zone CFR 2.0–2.5)

[1.05–1.38]; p=0.008).22 CFR can be impaired if basal coronary flow is high, diastolic time is reduced or intra-myocardial pressure is increased.23 Therefore, fluctuations in the resting haemodynamic status can lead to variability during repeat measurement. CFR is calculated from the principles of thermodilution by dividing the resting mean transit time by the hyperaemic mean transit time. A CFR of ≤2.0 is abnormal, with 2.1–2.5 reflecting a ‘grey-zone’ result.

Index of Microvascular Resistance

Coronary vascular resistance is mainly determined within the microcirculation. The apparent index of microvascular resistance (IMR) is the product of distal coronary pressure and hyperaemic mean transit time. An IMR if ≥25 is considered abnormal, with a few caveats: there is a weak correlation between IMR and subtended myocardial mass; and there is variation between ethnicities, with a lower cut-off suggested in Asians.24 IDP Step 2

Vasoreactivity testing Intracoronary acetylcholine

Pharmacological Vasoreactivity Testing

Acetylcholine is now the default agent for provocation testing.25 Okumura et al. demonstrated that intracoronary acetylcholine had 90% sensitivity and 99% specificity for diagnosing epicardial spasm.26

Epicardial spasm: ≥90% constriction

No spasm

Vasospastic angina

Non-cardiac symptoms

Microvascular spasm: <90% constriction; TIMI flow ≤2

Microvascular angina

CFR = coronary flow reserve; IDP = interventional diagnostic procedure; IMR = index of microvascular resistance; TIMI = thrombolysis in MI.

avoid artefactual pressure recordings. Thermodilution deflection curves and transit times should be inspected, with outlier and artefactual values replaced. The distribution of transit times should be within 0.1 second of each other. Adenosine can be administered as an IV infusion (140–210 µg/kg/min) or intracoronary bolus (50–200 µg). The intracoronary dose for the dominant coronary artery should be approximately halved to limit the possibility of transient heart block. Markers of hyperaemia should be confirmed: ‘ventricularisation’ and disappearance of the dicrotic notch in the distal pressure waveform; separation of the aortic and distal pressures; and symptoms (typically chest discomfort and/or dyspnoea). Changes in heart rate and blood pressure are less reliable indicators of hyperaemia. When stable hyperaemia with adenosine infusion is confirmed, FFR is measured and thermodilution transit times repeated. The same principles apply if using a Doppler/pressure wire to measure Doppler-derived average peak velocities at rest and hyperaemia.

Coronary Flow Reserve

Coronary flow reserve (CFR) reflects the vasodilator capacity of the whole coronary circulation, including the epicardial coronaries and microcirculation. The WISE study demonstrated that low CFR was an independent predictor for the composite endpoint of death, non-fatal MI, non-fatal stroke or hospitalisation for heart failure (HR 1.20; 95% CI

Acetylcholine is an endogenous neurotransmitter acting on muscarinic and nicotinic receptors. In blood vessels, its effects reflect responses from both the endothelium and smooth muscle cells. Acetylcholine is not licensed for parenteral administration so gaining informed consent should take account of the rationale for its use. Acetylcholine testing assesses the physiological response, which, in a healthy artery, should be vasodilatation. In the presence of endothelial dysfunction, the response may be micro- or macrovascular spasm. The hospital pharmacy should facilitate drug access, storage, transport and reconstitution. For the final stage of the IDP, intracoronary acetylcholine is infused via either the guiding catheter or a dedicated microcatheter. The benefit of a microcatheter is the theoretical avoidance of pan-coronary spasm. The CorMicA study demonstrated direct infusion using the guiding catheter was safe, and avoid the cost and risk of additional coronary instrumentation.6 Our protocol for acetylcholine provocative testing involves intracoronary infusion of incremental concentrations (10-6, 10-5, 10-4 mol/l) at 1 ml/min for 2 minutes using a mechanical pump, followed by a bolus of 100 µg (half dose for the dominant coronary artery) given over 20 seconds, with continuous monitoring of the ECG and patient. An alternative approach is manual infusions of 2 µg, 20 µg, 100 µg and 200 µg. If infusing into a ‘dominant’ coronary artery, consider halving the dose to limit potential bradyarrhythmia. Before starting each infusion, first fill the guiding catheter lumen with infusate to reduce any 'dead space' effect when the infusion begins. Afterwards, ensure gentle purging of the catheter following each infusion to avoid a sudden bolus of acetylcholine with the next injection of contrast. Vigilance is required during infusions, with intracoronary nitrates at hand to reverse any spasm. The half-life of acetylcholine is <15 seconds, with effects ceasing rapidly once the infusion is stopped.27 Coronary angiography at a projection without vessel foreshortening is acquired at baseline, then repeated after each infusion. The vessel luminal diameter is compared to its size at baseline. A diameter reduction of >20% suggests endothelial dysfunction (MVA), while ≥90% reduction

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INOCA for the Interventionalist Table 2: Guideline-recommended Treatments Based on Clinical Endotype Diagnosis

Treatment

Mechanism of Effect

Microvascular angina

β-blockers (nebivolol 2.5–10 mg once daily)

• ↓ Myocardial oxygen consumption • Antioxidant properties • Vascular smooth muscle relaxation • ↓ Myocardial oxygen consumption • Coronary microvascular dilator • Improves microvascular perfusion reserve index in microvascular angina

Calcium-channel blockers (amlodipine 10 mg once daily) Nicorandil (10–20 mg twice daily) Ranolazine (375–750 mg twice daily)

with reduced CFR

• Increases cellular tolerance to ischaemia by maintaining homeostasis • Improves CFR • ↓ Workload • May improve small vessel remodelling • ↓ Spontaneous and inducible epicardial coronary spasm via smooth

Trimetazidine (35 mg twice daily) ACE inhibitors (ramipril 2.5–10 mg once daily); angiotensin-receptor blockers if intolerant Vasospastic angina

Calcium channel blockers (verapamil 240 mg once daily or diltiazem 120–360 mg daily)

muscle relaxation

Nitrates (isosorbide mononitrate 20–120 mg daily) Nicorandil (10–20 mg twice daily) Mixed microvascular and vasospastic angina

Calcium channel blockers (amlodipine 10 mg once daily, diltiazem 90 mg twice daily or verapamil 240 mg once daily) Nicorandil (10–20 mg twice daily) Trimetazidine (35 mg twice daily) ACE inhibitors (ramipril 2.5–10 mg); angiotensin-receptor blockers if intolerant

Non-cardiac symptoms

Discontinue antianginal medication; consider continuing cardiovascular risk reduction medication (e.g. statin) if coronary artery disease present

Cardiovascular risk reduction Statins (e.g. atorvastatin 20–80 mg) Antihypertensives Lifestyle: smoking cessation, exercise, cardiac rehabilitation, Mediterranean diet, cognitive behavioural therapy

• ↓ Myocardial oxygen consumption • ↓ Spontaneous and inducible coronary spasm via epicardial vasodilatation • ↓ myocardial oxygen consumption • Coronary vasodilator effect • Vascular smooth muscle relaxation • ↓ Myocardial oxygen consumption • Coronary microvascular dilator • Increases cellular tolerance to ischaemia by maintaining homeostasis • Improves CFR • ↓ Workload • May improve small vessel remodelling • Cessation of unnecessary polypharmacy • Continue cardiovascular risk reduction • Consider referral to alternative specialty if appropriate • Improve coronary endothelial function • Reduced vascular inflammation • As per current hypertension guidelines • Improved exercise capacity and cardiac conditioning, weight reduction if overweight

Summary of European Association of Percutaneous Cardiovascular Interventions expert consensus 3 and European Society of Cardiology chronic coronary syndromes 2019 guideline4 for recommended treatment based on clinical endotype. CFR = coronary flow reserve. Adapted from: Kunadian et al. 2020.3 Used with permission from Oxford University Press.

suggests VSA. Semiquantitative analysis of antegrade contrast flow may be undertaken by calculating the TIMI (thrombolysis in MI) frame count, with >27 (images acquired at 30 frames/second) suggesting MVA (coronary slow-flow phenomenon from microvascular spasm).3

bradycardia are usually transient. Patient coughing manoeuvres can help maintain haemodynamic perfusion in the event of asystole.29 Atropine and isoprenaline should be readily available, with electrical pacing rarely necessary.

A pressure wire pullback should be performed at the end of the IDP to exclude significant (>0.03) signal drift. The IDP can be repeated in different coronary artery territories if false-negative results are suspected. Figure 2 highlights typical examples for each clinical endotype.

Treatments

Risks and Safety Considerations

The main risks of the IDP are those relating to standard coronary angiography, use of a guidewire and the physiological effects of acetylcholine including refractory coronary spasm, bradycardia and/or AF. The CorMicA study demonstrated that the IDP is feasible, safe and low risk in trained hands.6 Likewise, other studies demonstrated an incidence of cardiac arrhythmias during provocation testing comparable with that observed during spontaneous spasm (6.8% versus 7.0%).28 The monitoring set-up during invasive angiography facilitates safety. Vasospasm and

The goals of therapy are twofold: amelioration of symptoms; and reduction in cardiovascular risk. Linked stratified medical therapy guided by the IDP can improve angina and quality of life within a previously undifferentiated, heterogenous population.6,12 Guideline-recommended treatments based on clinical endotype are summarised in Table 2.3 Bairey Merz et al. have published a review of current and upcoming treatments in INOCA.30 Endothelial dysfunction typically precedes atherosclerosis, which mandates aggressive treatment of cardiovascular risk factors.31

Challenges in INOCA

INOCA testing, particularly the off-label use of acetylcholine, remains the remit of specific specialist centres at present, perpetuating limited experience in the wider community. Local arrangements are required for the supply of acetylcholine at each site, either as vials for reconstitution

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INOCA for the Interventionalist or as infusion-ready solutions from the pharmacy. The former option requires enhanced staff training, while the latter is more expensive. Patient reminders for abstinence of caffeine and vasoactive medication are needed during allocation of angiography appointments, to facilitate the option of vasoreactivity testing on the day. The management of INOCA often requires a period of optimisation; there is no one-size-fits-all panacea. Repeated clinical follow-up is necessary for individualised assessment and titration of medication to achieve the optimal patient-specific management plan.

Future Work

The true prevalence of INOCA in the general population remains unclear. Studies in cardiac catheterisation settings represent a highly selected and symptomatic subset, and fail to account for patients who are medically managed. While the CorMicA pilot was successful in demonstrating the utility of the IDP, larger-scale, international studies are needed to strengthen practice guidelines. To this end, the iCorMicA trial (NCT04674449) is currently recruiting. Studies are under way for microvascular-specific therapies, including endothelin receptor antagonist zibotentan (PRIZE study; NCT04097314); coronary sinus reducer stent (NCT02710435); and pressure-controlled intermittent coronary sinus occlusion (NCT03625869). 1. Ford TJ, Berry C. Angina: contemporary diagnosis and management. Heart 2020;106:387–98. https://doi. org/10.1136/heartjnl-2018-314661; PMID: 32054665. 2. Ford TJ, Corcoran D, Berry C. Stable coronary syndromes: pathophysiology, diagnostic advances and therapeutic need. Heart 2018;104:284–92. https://doi:10.1136/ heartjnl-2017-311446; PMID: 29030424. 3. Kunadian V, Chieffo A, Camici PG, et al. An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology working group on coronary pathophysiology & microcirculation endorsed by Coronary Vasomotor Disorders International. Eur Heart J 2020;41:3504–20. https://doi. org/10.1093/eurheartj/ehaa503; PMID: 32626906. 4. Neumann FJ, Sechtem U, Banning AP, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. https://doi. org/10.1093/eurheartj/ehz425; PMID: 31504439. 5. National Institute for Health and Care Excellence. Recentonset chest pain of suspected cardiac origin: assessment and diagnosis. London: NICE; 2016. https://www.nice.org.uk/cg95 (accessed 4 October 2021). 6. Ford TJ, Stanley B, Good R, et al. Stratified medical therapy using invasive coronary function testing in angina: the CorMicA trial. J Am Coll Cardiol 2018;72:2841–55. https://doi. org/10.1016/j.jacc.2018.09.006; PMID: 30266608. 7. Aziz A, Hansen HS, Sechtem U, et al. Sex-related differences in vasomotor function in patients with angina and unobstructed coronary arteries. J Am Coll Cardiol 2017;70:2349–58. https://doi.org/10.1016/j.jacc.2017.09.016; PMID: 29096805. 8. Tavella R, Cutri N, Tucker G, et al. Natural history of patients with insignificant coronary artery disease. Eur Hear J Qual Care Clin Outcomes 2016;2:117–24. https://doi.org/10.1093/ ehjqcco/qcv034; PMID: 29474626. 9. Maddox TM, Stanislawski MA, Grunwald GK, et al. Nonobstructive coronary artery disease and risk of myocardial infarction. JAMA 2014;312:1754–63. https://doi. org/10.1001/jama.2014.14681; PMID: 25369489. 10. Jespersen L, Hvelplund A, Abildstrøm SZ, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2012;33:734–44. https:// doi.org/10.1093/eurheartj/ehr331; PMID: 21911339. 11. Petrie KJ, Weinman J, Sharpe N, Buckley J. Role of patients’ view of their illness in predicting return to work and functioning after myocardial infarction: longitudinal study. BMJ 1996;312:1191–4. https://doi.org/10.1136/bmj.312.

Conclusion

INOCA remains a diagnostic and therapeutic challenge. There is growing evidence to support the use of adjunctive IDP in the assessment of INOCA, as reflected in the latest guidelines.4 Today’s interventionists are well placed to make a positive impact with more personalised care. The theoretical risk and added time of performing the IDP is outweighed by its benefits. More widespread adoption should be encouraged, as should its incorporation in training and professional standards.

Clinical Perspective

• Up to half of patients undergoing coronary angiography for

known or suspected angina have ischaemia with non-obstructed coronary artery disease, which is associated with impaired quality of life, higher morbidity and healthcare resource utilisation. • Interventionists are uniquely placed to offer gold-standard assessment of microvascular function and more personalised care through the interventional diagnostic procedure (IDP). • The IDP with linked stratified medical therapy improves symptom burden, quality of life, treatment satisfaction and illness perception.

7040.1191; PMID: 8634561. 12. Ford TJ, Stanley B, Sidik N, et al. 1-year outcomes of angina management guided by invasive coronary function testing (CorMicA). JACC Cardiovasc Interv 2020;13:33–45. https://doi. org/10.1016/j.jcin.2019.11.001; PMID: 31709984. 13. Medical Research Council. The MRC Framework for the Development, Design and Analysis of Stratified Medicine Research. Swindon, UK: MRC, 2018. https://mrc.ukri.org/ research/initiatives/precision-medicine/stratified-medicinemethodology-framework (accessed 4 October 2021). 14. Ong P, Camici PG, Beltrame JF, et al. International standardization of diagnostic criteria for microvascular angina. Int J Cardiol 2018;250:16–20. https://doi.org/10.1016/j. ijcard.2017.08.068; PMID: 29031990. 15. Crea F, Bairey Merz CNB, Beltrame JF, et al. The parallel tales of microvascular angina and heart failure with preserved ejection fraction: a paradigm shift. Eur Heart J 2017;38:473–7. https://doi.org/10.1093/eurheartj/ehw461; PMID: 27907892. 16. Berry C, Sidik N, Pereira AC, et al. Small-vessel disease in the heart and brain: current knowledge, unmet therapeutic need, and future directions. J Am Heart Assoc 2019;8:e011104. https://doi.org/10.1161/JAHA.118.011104; PMID: 30712442. 17. Sorop O, Merkus D, De Beer VJ, et al. Functional and structural adaptations of coronary microvessels distal to a chronic coronary artery stenosis. Circ Res 2008;102:795– 803. https://doi.org/10.1161/CIRCRESAHA.108.172528; PMID: 18292598. 18. Prinzmetal M, Kennamer R, Merliss R, et al. Angina pectoris I. A variant form of angina pectoris. Preliminary report. Am J Med 1959;27:375–88. https://doi.org/10.1016/00029343(59)90003-8; PMID: 14434946. 19. Ford TJ, Yii E, Sidik N, et al. Ischemia and no obstructive coronary artery disease: prevalence and correlates of coronary vasomotion disorders. Circ Cardiovasc Interv 2019;12:e008126. https://doi.org/10.1161/ CIRCINTERVENTIONS.119.008126; PMID: 31833416. 20. Williams RP, De Waard GA, De Silva K, et al. Doppler versus thermodilution-derived coronary microvascular resistance to predict coronary microvascular dysfunction in patients with acute myocardial infarction or stable angina pectoris. Am J Cardiol 2017;121:1–8. https://doi.org/10.1016/j. amjcard.2017.09.012; PMID: 29132649. 21. Glyceryl trinitrate 5 mg/ml sterile concentrate. Summary of product characteristics. EMC. 18 January 2021. https://www. medicines.org.uk/emc/product/3792/smpc (accessed 4 October 2021). 22. Pepine CJ, Anderson RD, Sharaf BL, et al. Coronary

microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia. Results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) Study. J Am Coll Cardiol 2010;55:2825–32. https://doi.org/10.1016/j. jacc.2010.01.054; PMID: 20579539. 23. Gould KL, Johnson NP. Coronary physiology beyond coronary flow reserve in microvascular angina: JACC stateof-the-art review. J Am Coll Cardiol 2018;72:2642–62. https:// doi.org/10.1016/j.jacc.2018.07.106; PMID: 30466522. 24. Suda A, Takahashi J, Hao K, et al. Coronary functional abnormalities in patients with angina and nonobstructive coronary artery disease. J Am Coll Cardiol 2019;74:2350–60. https://doi.org/10.1016/j.jacc.2019.08.1056; PMID: 31699275. 25. Beltrame JF, Crea F, Kaski JC, et al. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J 2017;38:2565–8. https://doi.org/10.1093/ eurheartj/ehv351; PMID: 26245334. 26. Okumura K, Yasue H, Matsuyama KK, et al. Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm. J Am Coll Cardiol 1988;12:883–8. https://doi.org/10.1016/0735-1097(88)904494; PMID: 3047196. 27. El-Tamimi H, Mansour M, Wargovich TJ, et al. Constrictor and dilator responses to intracoronary acetylcholine in adjacent segments of the same coronary artery in patients with coronary artery disease endothelial function revisited. Circulation 1994;89:45–51. https://doi.org/10.1161/01. cir.89.1.45; PMID: 8281679. 28. Takagi Y, Yasuda S, Takahashi J, et al. Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association. Eur Heart J 2013;34:258–67. https://doi. org/10.1093/eurheartj/ehs199; PMID: 22782943. 29. Jafary FH. Cough-assisted maintenance of perfusion during asystole. Can J Cardiol 2008;24:e76. https://doi.org/10.1016/ S0828-282X(08)70693-7; PMID: 18841266. 30. Bairey Merz CN, Pepine CJ, Shimokawa H, Berry C. Treatment of coronary microvascular dysfunction. Cardiovasc Res 2020;116:856–70. https://doi.org/10.1093/cvr/cvaa006; PMID: 32087007. 31. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004;109(23 Suppl 1):III27–32. https://doi.org/10.1161/01.CIR.0000131515.03336.f8; PMID: 15198963.

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Anterograde CTO Techniques

Advances in the Post-coronary Artery Bypass Graft Management of Occlusive Coronary Artery Disease Mohammed Shamim Rahman ,1 Ruben de Winter ,2 Alex Nap2 and Paul Knaapen

1. Department of Cardiology, Birmingham City Hospital, SWBH NHS Trust, Birmingham, UK; 2. Department of Cardiology, Amsterdam Medical Centre, VU Medical Centre, Amsterdam, the Netherlands

Abstract

Revascularisation of chronic total occlusion (CTO) represents one of the most challenging aspects of percutaneous coronary intervention, but advances in equipment and an understanding of CTO revascularisation techniques have resulted in considerable improvements in success rates. In patients with prior coronary artery bypass grafting (CABG) surgery, additional challenges are encountered. This article specifically explores these challenges, as well as antegrade methods of CTO crossing. Techniques, equipment that can be used and reference texts are highlighted with the aim of providing potential CTO operators adequate information to tackle additional complexities likely to be encountered in this cohort of patients. This review forms part of a wider series where additional aspects of patients with prior CABG should be factored into decisions and methods of revascularisation.

Keywords

Percutaneous coronary intervention, chronic total occlusion, coronary artery bypass grafting, saphenous vein graft, antegrade wire escalation, antegrade dissection re-entry, hybrid algorithm Disclosure: The authors have no conflicts of interest to declare. Received: 15 March 2021 Accepted: 7 June 2021 Citation: Interventional Cardiology 2021;16:e33. DOI: https://doi.org/10.15420/icr.2021.12 Correspondence: Mohammed Shamim Rahman, Department of Cardiology, Birmingham City Hospital, SWBH NHS Trust, Dudley Rd, Birmingham B18 7QH, UK. E: shamimrahman@doctors.net.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Coronary artery bypass grafting (CABG) surgery is a common method of coronary revascularisation and remains the standard of care in patients with multivessel coronary artery disease (CAD), as well as in those with diabetes.1 Since 2004, CABG numbers have been in decline in the UK, whereas the number of percutaneous coronary interventions (PCI) has shown a consistent increase year-on-year until a recent plateau.2 PostCABG patients now represent a significant proportion of patients who subsequently require PCI and represent a challenging cohort in terms of clinical frailty and anatomical complexity.3 In this review we discuss these challenges and specifically consider the subset of post-CABG patients presenting with chronic total occlusions (CTO) in their native coronary arteries.

Challenges in Post-CABG Patients Graft Failure

Although surgical success rates remain high, venous bypass graft patency rates remain the ‘Achilles’ heel’ of the long-term prognosis of surgical revascularisation. Whereas arterial revascularisation has been demonstrated as a superior, lasting method,4–6 venous bypass grafts do not withstand this test of time. Left internal mammary artery (LIMA) grafts can remain patent in 88–100% of patients at 15 years,7,8 a finding echoed by right internal mammary artery (RIMA) use, which retains excellent graft patency up to 10 years, with patency rates quoted at 81% or equivalent to the LIMA for identical coronary territories.8,9 However, saphenous vein grafts (SVG) have relatively poor patency rates.10,11 In their meta-analysis,

Athanasiou et al. compared SVG patency with radial artery graft patency.12 Of the seven studies examining patency rates after a median 5-year follow-up, four recorded SVG patency rates between 65% and 72%, whereas the others recorded higher rates (72–91%).12 In a study of 1,074 patients, 10-year SVG patency rates were 61% when compared to LIMA grafts, where the patency rate was recorded at 85%.13 More contemporary data are available from the COMPASS-CABG substudy and POPular CABG trials, both of which used CT coronary angiography (CTCA) to assess SVG patency 1 year after surgery.14,15 In the COMPASSCABG substudy, patients were treated with rivaroxaban, with or without aspirin or aspirin alone, with an overall 9.6% occlusion rate of all SVG studied.14 In the POPular CABG trials, graft occlusion occurred in 9.9% of all grafts, with no significant improvement despite the addition of ticagrelor antiplatelet therapy.15 CTCA has allowed non-invasive assessment of graft patency, and its wider use may uncover further aspects of post-surgical coronary anatomy and graft viability not previously appreciated.16,17 In particular, attention should be paid to the increased likelihood that patients with existing CTOs and multivessel disease possess higher anatomical and clinical risk scores and are thus more likely to be referred for CABG in the first instance.18–20 Yet, postoperative angiographic assessment in patients who underwent both on- and off-pump CABG for CTOs has revealed that grafts placed on non-left anterior descending artery (LAD) collateralised CTOs suffer from extremely poor patency rates

Post-CABG Management of Occlusive CAD at 1-year follow-up, as low as 22–24%, which is an unacceptably low graft viability rate that should call into question the rationale for CABG in the presence of a non-LAD CTO.21

Revascularisation Complexity

Christopoulos et al. describe the post-CABG population as older, more likely to suffer from diabetes and have suffered from previous MI.22 CTOs are more prevalent in this subgroup of patients than in those without prior CABG, with registry data demonstrating the presence of a CTO in 54% of evaluated post-CABG patients.23 Patients with a CTO and symptoms relating to ischaemia with myocardial viability do benefit from revascularisation versus optimal medical therapy alone, with improvements in both symptom burden and quality of life.24 However, they are less likely to receive revascularisation therapy, likely due, in part, to the perceived complexity of the procedure.23 In the Canadian Multicenter CTO Registry published by Fefer et al., of 1,697 patients identified with a CTO (and no prior CABG), medical therapy was opted for in 44% of patients, with 26% undergoing CABG (89% had a bypass graft on the CTO vessel) and 30% undergoing PCI. CTO PCI was attempted in only 31% of these patients and CTO success was achieved in only 24% of all patients undergoing PCI.23 This registry (2008–2009) suggested the presence of CTOs to be approximately 18% of all patients with CAD, and yet just under half these patients received medical therapy alone, one-quarter received surgical revascularisation and the remainder underwent PCI.23 This ‘interventional paradox’ will see some patients denied revascularisation for symptoms due to anatomical complexity and the perceived complexity of PCI. Furthermore, post-CABG patients will represent additional challenges when re-presenting with angina pectoris: they are likely to be older, have more comorbidities and have more complex coronary lesion characteristics, and for many, repeat CABG is not feasible due to excessive surgical risk compared with CABG-naïve patients.3,25–30

Saphenous Vein Graft Intervention

Therefore, in post-CABG patients, PCI remains the only strategy for repeat revascularisation, yet the presence of a previous bypass graft creates additional challenges to conventional PCI. While medical therapy can be a good first option for the treatment of angina, PCI for moderate SVG stenoses when compared to optimal medical therapy (OMT) can be effective, with lower rates of major adverse cardiovascular events (MACE) at 1-year follow-up in the VELETI I trial.31–33 Although the VELETI I trial was a hypothesis-generating, small, randomised pilot trial, it put forward the concept of ‘plaque sealing’ of moderate, non-significant atheromata in SVGs, which are thought to undergo accelerated atherosclerotic disease progression compared with native vessels.33 The subsequent larger randomised controlled VELETI II trial did not demonstrate any reduction in clinical endpoints in SVG PCI with drug-eluting stents (DES) at the 3-year follow-up compared with OMT in these so-called ‘intermediate’ lesions, although the pooled analysis of both VELETI trials may yet support the controversial concept of plaque sealing.34,35 Percutaneous treatment of SVGs accounts for between 5% and 10% of all PCIs.36–42 Although, unsurprisingly, the vast majority of SVG PCIs are performed within the body of the graft, approximately one-fifth of graft lesions occur at the aorto-ostial anastomosis and one-sixth occur at the distal anastomosis.43 Acute thrombotic SVG occlusion must be managed in the same manner as native coronary occlusion and, although procedural success tends to be high, mortality, recurrent acute coronary syndrome (ACS) and the need for revascularisation within the short to medium term remains significant.42,44 Preference is given to revascularising the native coronary artery over SVG by existing guidelines on myocardial

revascularisation.1 The paucity of data for this recommendation has led to development of the PROCTOR trial, a multicentre, multinational European randomised control trial, which will randomise patients to native vessel or SVG PCI, with results expected in 2027.45 The physiology of SVG failure is not fully understood, but it is thought these grafts are poorly adapted to arterial flow and the pathobiology of SVG degeneration results in a friable vessel with atheromatous debris to contend with.46,47 Additional challenges include the potential for embolisation of this debris into distal epicardial and coronary microcirculatory vasculature, resulting in the plugging of capillaries, increasing the prospect of the no-reflow phenomenon and associated risk of MI and subsequent in-hospital mortality.48–50 The routine use of distal embolic protection devices (DPD) has shown potential to significantly reduce periprocedural MI rates, but no significant reduction in in-hospital mortality could be demonstrated.51–54 However, these devices are cumbersome to deploy and, as such, their use has been historically limited.55,56 Furthermore, several observational studies and large registry data have shown conflicting results.57,58 Thus, the strength of recommendation for the use of DPD for SVG PCI was downgraded in the most recent update of the European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) guidelines on myocardial revascularisation to a Class IIa, level of evidence B, recommendation.1 Female sex, lesion length, extensive degenerative change and high plaque volume in diseased SVGs predict 30-day MACE.59,60 Periprocedural MI (as defined by a rise in creatine kinase (CK)-MB between ×1 and ×5 the upper limit of normal) was a stronger predictor of adverse outcome than similar cardiac enzyme values following SVG PCI and a powerful predictor of late cardiovascular mortality in an albeit dated study, with the overall rate of periprocedural MI reported as 15%.61 Periprocedural increases in CK-MB following SVG PCI are unsurprisingly significantly greater when no-reflow occurs (43% versus 4%, p<0.001) with probable thrombus, ACS presentation, graft degeneration and graft ulceration independent predictors of no-reflow.48 More contemporary studies of SVG PCI tend to use DPD, such as the post hoc analysis of the DIVA trial comparing direct stenting against stent deployment with or without balloon inflation (either prior to and/or after stent implantation).62 Patients were recruited to the DIVA trial between 2012 and 2015 and DPD use was >70% in both groups. Rates of periprocedural MI were low, at 4% of total lesions treated and 5% of patients treated.62 The use of DES in SVGs is now supported by a number of trials, all demonstrating poor longevity following treatment with plain old balloon angioplasty and covered stents.63–66 DES is advocated for SVG PCI due to lower rates of repeat revascularisation compared with the use of bare metal stents, although clinical outcome data remain conflicted, with only a limited number of randomised trials available.1,52,53,67–69 In the absence of randomised control data comparing SVG and native vessel PCI, registry data suggest SVG PCI remains inferior to native vessel PCI, with higher MACE rates, principally driven by MI and revascularisation rates, at 1 year.70 A history of previous bypass graft surgery is associated with a higher risk of restenosis, and SVG as the PCI target is independently associated with an increased risk of very-late stent thrombosis.71,72

Chronic Total Occlusion Revascularisation in Post-CABG Patients

Although there remains a paucity of data from randomised control trials supporting CTO revascularisation, symptom- and, where relevant, myocardial viability-driven revascularisation has been established by the EuroCTO Trial.24 This approach is supported by the latest guidelines.1

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Post-CABG Management of Occlusive CAD The DECISION-CTO trial did not report an improvement in quality of life outcomes, although this trial fell short in recruitment and thus was stopped early.73 Although the trialists have been congratulated for the large number of patients randomised, several limitations have been identified, including a lack of baseline symptoms, cross-over to the CTO PCI group (from the non-CTO PCI group) and the non-inferiority and prePCI randomisation design, in addition to the underpowered study.74 CTOs in the presence of bypass grafts are often longer in length with a higher calcific burden and diffuse atherosclerotic disease.75,76 These CTOs are themselves complex, as graded by the frequently adopted Multicenter CTO Registry of Japan (J-CTO) score, with higher J-CTO scores than in nonCABG patients, and suffer from greater anatomic distortion, with threedimensional tenting effects exerted on the native vessel at the distal graft anastomosis.22,28,77–81 It is unclear whether this is the result of a pre-existing heavy burden of disease that necessitated CABG revascularisation in the first instance, accelerated atherosclerosis or the presence of the distal graft anastomosis resulting in disease progression due to competitive flow.82–86 In addition to these anatomical and pathophysiological factors, patient characteristics must also be considered. Evolution of knowledge, techniques and, perhaps most importantly, equipment has facilitated higher rates of success in CTO revascularisation. Among these, the introduction of microcatheters has dramatically altered the ability of operators to safely and successfully cross CTOs and these should be used in all CTO PCI cases regardless of complexity. Microcatheters are further elaborated on below. Revascularisation by redo CABG in patients with prior CABG is not without jeopardy, with a two- to fourfold increased risk compared with first-time CABG.87,88 However, mortality was comparable between PCI and redoCABG for these patients at 3 years, with higher rates of revascularisation in PCI patients.39,89,90 Post-CABG patients can suffer cardiac tamponade at the same frequency as non-CABG patients.91 In addition, prior CABG is associated with reduced event-free survival, with higher rates of cardiac death and MACE demonstrated by univariable analysis and higher rates of MACE demonstrated by multivariable analysis, driven largely by target vessel revascularisation.28 ‘Dry tamponade’ has been recognised as a significant complication of coronary perforation in post-CABG patients, caused by the extravasation of blood within the myocardial wall or adjacent structures within a pericardium with more adhesions.92,93 Inhospital complications are also more frequent in prior CABG patients undergoing CTO PCI than in non-CABG patients, as reported in a multicentre registry of 2,058 patients (prior CABG n=401; non-CABG n=1,657), with higher rates of major complications (3.7% versus 1.5%), any perforation (12% versus 5.2%), periprocedural MI (2.0% versus 0.5%) and procedure-related deaths (0.8% versus 0.1%).27 In a smaller study of 470 patients, contrast-induced nephropathy was more common in prior CABG patients (4.6% versus 1.0%).28 Risk scores developed to predict CTO PCI success, such as the RECHARGE-Score and Clinical and Lesion-related score (CL Score), attribute higher scores to post-CABG patients, reflecting these adverse events.94,95 Of note, previous CABG will preclude rapid and safe sternotomy if a complication arises following or during PCI, and this may have contributed to some of the morbidity seen in these scoring systems.96 Having a sufficiently experienced team to manage complications in post-cardiotomy patients in high-volume PCI centres is essential. The recognition of longer procedures and older and potentially frailer patients with reduced renal function should be considered when evaluating the benefits of potential percutaneous CTO revascularisation, and the ways in which this can be

mitigated are further elaborated on below. Conversely, the presence of patent grafts, in addition to providing potential retrograde conduits, can reduce ischaemia in the distal target territory and, in the case of a patent LIMA, reduce the consequences of anterior wall ischaemia from inadvertent left main coronary artery dissection. Factoring in prior CABG, the presence of a non-proximal lesion position, proximal tortuosity (moderate/severe) and distal cap ambiguity, described as the ‘J-CTO+ model’ improved the power of the J-CTO score in predicting successful CTO crossing.78 These factors provide additional challenges over and above what may be encountered in native vessel CTO PCI in the absence of graft anastomoses. Understanding these potential challenges up front allows the operator to select appropriate techniques and tools to approach CTO cases where SVGs are involved. Since early pioneers such as Kaltenbach and Reifart in Frankfurt and Rutherford in Kansas City described their experiences in CTO treatment, significant advances in the understanding of pathology, technology and the formulation of accepted standards and techniques have been made, resulting in significantly improved long-term treatment success rates.94,97,98 Original descriptions of CTO PCI were fraught, with difficult, long procedures and prohibitively high reocclusion rates.99,100 Early concepts led to the subsequent development of contemporary tools now in use. The formation of ‘CTO Clubs’, such as the Japanese CTO Club in 1991 and the European equivalent in 2006, improved the sharing and dissemination of knowledge and the development of techniques to improve success rates and reduce periprocedural morbidity. The development of registries such as PROGRESS-CTO and RECHARGE, randomised trials and regional consensus documents have provided a basis for understanding accepted techniques and monitoring contemporary practice, including complication and morbidity rates.24,73,94,101,102 Among these developments, the hybrid algorithm is the currently accepted consensus strategy being used by high-volume, experienced leaders in the field.103 This demands the ability to adopt both antegrade and retrograde approaches to CTO crossing to ensure the optimal use of available techniques with contemporary equipment, with further results from adopting this approach still being reported. The RECHARGE Registry is thus far the largest of its kind, with over 1,200 patients recruited from European centres to demonstrate both high procedural success rates and low adverse event rates when the hybrid algorithm has been used by experienced operators in high-volume centres.97 It is therefore important to recognise the potential benefits gained through the ability to adopt different strategies to recanalise a CTO and, most pertinently, recognise when to opt for a specific strategy. Retrograde techniques are most often necessary in post-CABG patients due to the complexities described above, usually in conjunction with antegrade techniques that then form the hybrid algorithm approach to these patients.22 Retrograde crossing is more common in post-CABG patients where the SVG can often be used as the collateral channel.22 Whether the native vessel CTO or, indeed, the SVG should be treated in post-CABG patients with graft degeneration remains unclear. Current ESC guidelines recommend PCI as the preferred method of revascularisation in patients with a large burden of ischaemia or severe symptoms due to disease progression or late graft failure.1 However, evidence to support this position is sparse, with limited data implicating prior CABG with poor outcomes, as discussed above, with patient clinical characteristics rather than revascularisation method predominantly determining outcome and anatomical considerations dictating the method of revascularisation.29,71,72

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Post-CABG Management of Occlusive CAD Table 1: Comparison of Chronic Total Occlusion CABG-Naïve and Post-CABG patients Prior CABG No Prior CABG p-value (n=176) (n=320) Target vessel (%)

0.07

Right

Left anterior descending

Left circumflex

Other

Moderate/severe calcification (%)

<0.001

Moderate/severe tortuosity (%)

<0.001

Lesion length (mm); median (IQR)

39 (28–67)

30 (20–40)

<0.001

Lesion age (months); median (IQR) 44 (6–90)

10 (3–42)

<0.01

Previous CTO attempt (%)

0.61

J-CTO score; mean (±SD)

3.12 ± 1.03

2.41 ± 1.21

<0.001

CABG = coronary artery bypass grafting; CTO = chronic total occlusion; IQR = interquartile range. Source: Christopoulos et al.22 Adapted with permission from Elsevier.

Figure 1: Applications and Outcomes Following the Use of the Hybrid Algorithm Stratified by J-CTO Score 100% 94% 75%

81% 74%

50% 37% 29%

25%

19% 10% 0%

AWE

ADR J-CTO ≤1

AWE

ADR J-CTO ≥2

Attempted

Success

Use and success of antegrade wire escalation (AWE) and antegrade dissection re-entry (ADR) in the RECHARGE Registry of Hybrid Algorithm CTO crossing. Source: Maeremens et al.97 Adapted with permission from Elsevier.

Retrospective and comparative studies have attempted to address this.70,104 However, the PROCTOR trial will be the first randomised trial comparing SVG PCI to native vessel PCI and should help in the decision making for patients with SVG degeneration and stenosis.45

Antegrade Techniques

Operators should be able to call on existing, established techniques of antegrade CTO crossing. These will include antegrade wire escalation (AWE) and/or antegrade dissection re-entry (ADR). Some of these techniques are highlighted below, with supporting evidence discussed. CTOs in the post-CABG cohort exhibit a higher calcific burden, increased tortuosity, longer lesion length and established occlusions for a longer duration, resulting in higher J-CTO scores22 (Table 1).22,76 Although AWE can be a successful strategy and is the default in most cases of CTO,

particularly when J-CTO scores are ≤1 (Figure 1), the increased complexity likely to be present in post-CABG patients will often necessitate additional and adjunctive hybrid algorithm techniques.78,97 Antegrade techniques are highly useful in many CTO cases with differences in pathology within the CTO body, but must contend with the presence of more complex, calcified distortions of the artery with severe negative remodelling present than in short-duration CTOs in patients without prior CABG.76 In the RECHARGE Registry, less complex lesions (J-CTO score ≤1) were successfully crossed using an AWE approach with high success rates (86%), whereas ADR and retrograde techniques were often used as bailout strategies with reasonable success.97 However, in more complex lesions (J-CTO score ≥2), AWE was a less successful strategy (50%), requiring ADR and retrograde bailout approaches more frequently.97

Planning Revascularisation

Up-front careful analysis of the coronary angiogram is key to understand potential challenges likely to be encountered during the CTO PCI and can improve success rates considerably.105 The coronary angiogram for the CTO should be acquired without digital magnification in order to visualise the entire course of the vessel, with a long acquisition allowing full visualisation of any antegrade flow either through the CTO or antegrade bridging collaterals into the distal vessel. Large side branches and relevant bifurcations should be noted to help decide which strategy should be used. Where graft anastomoses are present beyond the distal cap of the CTO and where the graft remains patent, antegrade injection along the graft (again without digital magnification) should be used to better visualise the course of the vessel, although this may not be fully appreciated by invasive coronary angiography alone. If dual catheter injections are possible, simultaneous injections first down the patent graft, followed by the native coronary, can provide useful information on occlusion length and potential distal landing zones should an ADR (or, indeed, retrograde) strategy be used. Complex revascularisation attempts, particularly when prior failure has occurred, should be discussed with experienced CTO operators in high-volume centres where familiarity with the hybrid algorithm can be used to establish higher success rates.78,97 Growing evidence supports the use of CTCA as an effective tool for CTO procedural planning in both CABG-naïve and post-CABG patients.106–108 However, CT can have limitations here, particularly when high calcium burdens are encountered, making interpretation challenging, which is more likely in post-CABG patients.43,109 The CT-RECTOR study assessed the predictive value of successful CTO crossing with prior CTCA and was validated against the J-CTO score, suggesting the CT-RECTOR scoring system provided additive data aiding a successful procedure and optimising procedural time.107,108 However, post-CABG patients comprised only 17% and 11% of those included in the studies and, as such, the data should be interpreted with caution in this cohort. CTOs that have developed in post-CABG patients may have developed multiple native collaterals prior to or since graft degeneration and, as such, visualising the distal vessel may prove challenging. This can be overcome by using retrograde injections from both the diseased graft and contralateral native coronary artery, necessitating the use of an additional vascular access point and a third guide catheter.

Wires

Antegrade techniques use advances in coronary angioplasty wire technology allowing greater options for the operator. These improvements provide the operator with wires with greater torque, steerability and

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Post-CABG Management of Occlusive CAD tactile feedback, as well as improvements in wire tip force, and thus greater potential penetration strength. Wire escalation and success in this manner depends on a good understanding of wire properties. Wires will, in general, be hydrophobic, hydrophilic or polymer jacketed, with the latter providing the greatest lubricity, with the pay-off a reduction in tactile feel. Some wires will combine these features, allowing a balance of both ‘slip’ through lesions while allowing the tip to grip lesions and still provide some tactile feedback. It is usual to advance a ‘workhorse’ wire to the lesion, then escalate by exchanging to an appropriate wire, determined by the operator’s appreciation of the occlusion characteristics. Microchannels and loose tissue through the body of the CTO may be accessed via the proximal cap and, as such, a light yet slippery (hydrophilic or polymer-jacketed) wire with high torque response may be selected to successfully traverse the CTO. Histological findings from a sudden coronary death registry have provided insights into CTO lesion morphology in individuals with and without prior CABG.76 Histological parameters were used to further subdivide CTOs into those with histological parameters suggestive of a ‘short’ or ‘long’ duration and compared with those present in individuals where CABG had been performed at least 2 years prior to autopsy. Although no significant difference was demonstrated between these individuals, a tapered distal cap was more commonly reported in CTOs in prior CABG individuals, whereas an abrupt pattern was noted in the proximal cap, a finding also noted in the ‘long’-duration CTOs examined.76 Tapered proximal occlusions feature loose fibrous tissue with small microvessel recanalisation and so may be more amenable to wire crossing.110 Therefore, a retrograde approach to cross the cap and access the CTO body may be required in prior CABG patients, with heavier, more penetrative wires necessary to cross abrupt (blunt) caps. Gaia wires (Asahi Intecc) are a dedicated family of CTO wires that improve penetration while retaining tactile feedback due to their design featuring a ‘microcone’ tip.111 Heavier tip force and penetrative wires may be required to engage and cross the proximal and distal caps, which are formed of denser tissue than the body of the CTO. Tip loads vary from workhorse wires, which are typically ≤1 g, to gradual increases in tip loads as high as 40 g with the Astato XS 40 wire (Asahi Intecc), which delivers an equivalent penetration force of 796.2 kg/inches2.79 Caution must be exercised when traversing the CTO body with highly penetrative wires, particularly in tortuous and ambiguous vessels where tactile feedback is at a minimum. This is more apparent in post-CABG patients, where the distal graft anastomosis can alter vessel anatomy and result in tenting of the distal vessel. AWE demands an appreciation for wire properties so they are selected to tackle anticipated challenges likely to be encountered. Furthermore, AWE demands an understanding of when to escalate, when to de-escalate and subsequently when re-escalate, if and when appropriate. More detailed information regarding the specifics of wire choice when escalating in an antegrade fashion is available in the antegrade CTO book by Spratt et al.79

Antegrade Dissection Re-entry

When the CTO plaque cannot be traversed through the proximal cap or through the body of the CTO due to obstructions through an antegrade manner, it is often necessary to switch to an ADR strategy. The higher burden of calcium in post-CABG patients may represent one of these obstructions that cannot, despite the use of high-tip-force wires and adjuncts (elaborated on below), be crossed through in a true lumen-tolumen fashion.76 To perform ADR, the subintimal space must be accessed, and an ‘umbrella’ shape is often used on a polymer-jacketed wire to drive the wire forward in a knuckle fashion to access the subintimal space with relative safety. Caution should be exercised when the subintimal

space is accessed towards the distal graft anastomosis to ensure the dissection plane does not extend to or beyond this anastomosis, creating haematoma and thereby potentially occluding graft flow into the distal vessel. The plane of dissection created in this manner should be kept to a short distance from this area and re-entry into the distal true lumen should be attempted in a previously identified distal landing zone. This can be facilitated by using the Bridgepoint System (CrossBoss coronary catheter and Stingray LP CTO re-entry system; Boston Scientific), which provides a more controlled manner with which to advance equipment through the subintimal space with a smaller dissection plane created and targeted re-entry into the distal lumen, demonstrating higher rates of success than the less controlled knuckle wire technique.97 Dual-injection angiography allows an appropriate distal landing zone to be chosen, ideally proximal to the distal graft anastomosis so as not to compromise graft flow (when patent). ADR may not be the ideal strategy when the re-entry zone from the subintimal space back into the true vessel lumen is within 10 mm before the distal graft anastomosis or important side branches due to the risk of extension of the dissection plane and the resulting occlusion of these branches.112 Whether the subintimal space is accessed intentionally during ADR or inadvertently during attempted AWE, antegrade contrast injections should be avoided in order to minimise hydraulic extension of the subintimal space, resulting in compression of the true lumen and thereby reducing the likelihood of successful reentry.80 Techniques, such as STAR (Sub-intimal TrAcking and Reentry) and LAST (Limited Antegrade Subintimal Tracking), are recognised alternative techniques to traverse the subintimal space and then re-enter into the distal lumen, but are not favoured over the CrossBoss/Stingray system due to a lack of predictable longer-term success.113–115 It is important to recognise the need for at least a 7 Fr system to facilitate the passage and exchange of ADR equipment. Caution must be exercised when using ADR near side branches. Wires, and subsequently microcatheters, will tend to follow the path of least resistance and, as such, can follow subintimal tracks to enter and dissect side branches, particularly hazardous when antegrade contrast injections are prohibited and so these branches cannot be adequately visualised. Targeted re-entry by identifying a suitable distal landing zone for luminal re-entry and utilising the Stingray balloon, for instance, can help avoid dissection extension and side branch compromise. The CrossBoss catheter features a blunt, atraumatic, 1.0 mm tip and can safely traverse the subintimal plane, but it should not be used as an initial strategy to engage the proximal cap, particularly when ambiguous with multiple bridging collaterals, in the presence of extreme vessel tortuosity or when the vessel course is unclear. The use of a knuckled wire, guide catheter support systems (discussed below) and anchor balloons in proximal side branches can enhance support to enable passage of the CrossBoss catheter and delivery of the Stingray balloon. Once in the subintimal space, the CrossBoss will rarely exit due to the low resistance of the surrounding structures, but short segments of intimal tracking can be evident.80,97 The CrossBoss catheter is not steerable and, as such, advancement through the target vessel structure should be regularly monitored with non-contrast fluoroscopy in orthogonal planes during controlled advancement. Retrograde injections can be of use to ensure the CrossBoss moves in synchrony with the architecture of the visualised distal vessel, so-called ‘dancing’ with the target zone for luminal reentry. The CrossBoss will track the outer curve of the vessel and, as such, can pass into small side branches, which, if unrecognised

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Post-CABG Management of Occlusive CAD prior to further advancement, can result in vessel exit and coronary perforation, a non-negligible complication contributing to a high burden of morbidity and mortality in this small minority of patients.116 In the event of the CrossBoss entering a side branch, it should be withdrawn and a guidewire used to track beyond the side branch ostium, allowing the CrossBoss to then be delivered beyond this (wire redirect).80 In the event that wire crossing beyond the side branch is not possible, a knuckled wire can be used to cross the side branch then redeliver the CrossBoss and attempt advancement once again (knuckle redirect).80 Should this also not be successful, a small balloon with a 1:1 ratio to the side branch can be placed in the side branch ostium to deflect passage of a knuckled guidewire into the side branch subintimal space or, alternatively, a dual lumen catheter can be used to allow a second guidewire to cross beyond the side branch, thereby enabling advancement of the CrossBoss also beyond the side branch ostium, where it can then be advanced ahead of the guidewire.80

Adjunctive Equipment

Adequate support is key to overcoming the proximal and distal caps. This comes initially from the choice of vascular access. Femoral access affords larger bore access (up to 8 Fr commonly used) with the option of long sheaths to overcome iliac and aortic tortuosity. Biradial access may also allow insertion of a 7 Fr sheath, particularly when using slender sheaths that reduce the outer diameter by 1 Fr. Therefore, appropriate guide catheter selection is imperative, and guide catheters should be selected specifically for graft access where retrograde approaches or distal landing zone visualisation is necessary. Adjunctive support systems, such as guide catheter extensions, provide additional support to aid cap puncture, but are particularly beneficial during ADR. Advancement of the guide catheter extension into the coronary artery to the point at which endothelial dissection occurred can reduce influx of blood into the subintimal space, thereby reducing haematoma formation and subsequent compression of the true lumen. Re-entry beyond the distal cap is therefore aided using a guide catheter extension, maintaining luminal size for a greater likelihood of success into the true lumen. PostCABG CTO crossing may require multiple wire changes in AWE or ADR approaches, particularly when using knuckle wires or the CrossBoss catheter; as such, equipment allowing rapid exchange with balloon trapping aids efficiency. The Trapliner (Teleflex) guide extension catheter features a proximal balloon that aids this without the need for additional balloon trapping within the guide catheter system and can be a useful tool in cases such as post-CABG CTO revascularisation. In longer CTOs, a retrograde approach using both retrograde dissection re-entry (RDR) and ADR techniques may be necessary.78,97,98 RDR will involve accessing the subintimal space either distal to or through the distal CTO cap, and the reverse controlled antegrade and retrograde tracking (reverse CART) technique is currently the dominant RDR technique, with high success rates.117 The antegrade aspect to reverse CART involves ADR to facilitate overlapping knuckle wires followed by balloon dilation of the subintimal space to connect the common space between the retrograde and antegrade dissection planes. Following this, retrograde wiring of the guide catheter can be performed should the reverse CART be performed in the proximal portion of the vessel or if more distal a guide catheter extension can be advanced to the point of antegrade dissection (as described above) and facilitate efficient retrograde wiring of the antegrade guide.

Microcatheters have greatly improved the efficiency of wire exchange but also provide additive penetrative forces that can be applied to highresistance areas within the CTO. Each microcatheter retains specific properties that allow engagement into the proximal cap and can provide support for microcatheter and wire advancement with exchange when necessary. This can reduce friction on the wire through the body of the CTO and allow improved torque transmission.79 Microcatheters vary in their construction and so possess specific properties in terms of their size, lubricity, push force and the ability to track the wire and vessel. Microcatheters can be categorised as coil and non-coil based, with braided and non-braided catheters suited to different levels of penetration force and anatomy. Further details and comparisons of selected microcatheters can be found in the antegrade CTO book by Spratt et al. (chapter 7, section 20).79 As described above, calcium is a prominent feature in post-CABG patients. As such, it is essential to have calcium modification and imaging tools available and to use them where necessary. Rotational atherectomy (‘rotablation’) and, more recently, intravascular lithotripsy (IVL; Shockwave Medical, Fremont, California) provide tools to modify calcium, whereas intravascular imaging tools, such as intravascular ultrasound, are critical tools required to understand the calcium burden, pattern and location and the interval effects of calcium modification.118–120 Other available calciummodification tools include cutting, scoring and high-pressure balloons. It may be necessary to use these tools in conjunction with each other to allow successful CTO crossing and optimal stent placement in CTO vessels with a high calcium burden.

Deliberate Vein Graft Sacrifice

Following successful revascularisation of CTOs in post-CABG patients, consideration should be given as to whether a patent SVG will provide excessive competitive flow to the distal vessel and therewith reduce longterm patency rates in the reconstructed native vessel. In a retrospective analysis of consecutive post-CABG patients where deliberate SVG sacrifice was performed, mostly by using vascular plugs, Wilson et al. demonstrated this to be a safe and effective method, with high success and low periprocedural complication rates, in these patients.121 Although more data are still needed to demonstrate whether this technique can improve long-term revascularised CTO vessel patency, consideration should be given to this approach in selected cases.

Conclusion

CTO crossing has improved with available data, advances in technology and techniques, among which the hybrid algorithm has played a crucial role, resulting in high success rates and, importantly, excellent longterm outcomes. Understanding the challenges of CTO revascularisation in post-CABG patients in terms of anatomical and lesion characteristics and clinical patient factors is necessary to prepare operators for selecting appropriate strategies and techniques that it may be necessary to have available in the operator armamentarium for successful CTO crossing and outcomes. Older, frailer patients with multiple comorbidities and more complex, established lesions with increased anatomical variance will need to be appreciated and contended with. Antegrade CTO crossing in these patients is possible, yet it is important to recognise the need to have retrograde options available, particularly because vein grafts can act as excellent conduits to the distal vessel. Experienced operators and highvolume centres will offer these patients a good chance of improvements in symptoms and quality of life, the essence of CTO treatment.

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PMID: 22828774. 91. Kinnaird T, Anderson R, Ossei-Gerning N, et al. Coronary perforation complicating percutaneous coronary intervention in patients with a history of coronary artery bypass surgery. Circ Cardiovasc Interv 2017;10:e005581. https://doi.org/10.1161/circinterventions.117.005581; PMID: 28916604. 92. Vetrugno V, Sharma H, Townend JN, Khan SQ. What is the cause of hypotension? A rare complication of percutaneous coronary intervention of a chronic total occlusion: a case report. Eur Heart J Case Rep 2019;3:1–5. https://doi. org/10.1093/ehjcr/ytz184; PMID: 32123803. 93. Vescovo GM, Zivelonghi C, Scott B, Agostoni P. Percutaneous coronary intervention for chronic total occlusion. US Cardiol 2020;14:e11. https://doi.org/10.15420/ usc.2020.10. 94. Maeremans J, Spratt JC, Knaapen P, et al. Towards a contemporary, comprehensive scoring system for determining technical outcomes of hybrid percutaneous chronic total occlusion treatment: The RECHARGE score. Catheter Cardiovasc Interv 2018;91:192–202. https://doi. org/10.1002/ccd.27092; PMID: 28471074. 95. Guelker JE, Bansemir L, Ott R, et al. Validity of the J-CTO score and the CL-score for predicting successful CTO recanalization. Int J Cardiol 2017;230:228–31. https://doi. org/10.1016/j.ijcard.2016.12.165; PMID: 28041697. 96. Potter BJ, Matteau A, Noiseux N, Mansour S. High stakes: CTO-PCI in the post-CABG patient. Can J Cardiol 2018;34:238–40. https://doi.org/10.1016/j.cjca.2017.12.022. 97. Maeremans J, Walsh S, Knaapen P, et al. The hybrid algorithm for treating chronic total occlusions in Europe: the RECHARGE registry. J Am Coll Cardiol 2016;68:1958–70. https://doi.org/10.1016/j.jacc.2016.08.034; PMID: 27788851. 98. Wilson WM, Walsh SJ, Bagnall A, et al. One-year outcomes after successful chronic total occlusion percutaneous coronary intervention: the impact of dissection re-entry techniques. Catheter Cardiovasc Interv 2017;90:703–12. https://doi.org/10.1002/ccd.26980; PMID: 28296045. 99. Kahn JK, Hartzler GO. Retrograde coronary angioplasty of isolated arterial segments through saphenous vein bypass grafts. Cathet Cardiovasc Diagn 1990;20:88–93. https://doi. org/10.1002/ccd.1810200205; PMID: 2354520. 100. Kaltenbach M, Hartmann A, Vallbracht C. Procedural results and patient selection in recanalization of chronic coronary occlusions by low speed rotational angioplasty. Eur Heart J 1993;14:826–30. https://doi.org/10.1093/eurheartj/14.6.826; PMID: 8325312. 101. Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS-CTO). 2014. https:// clinicaltrials.gov/ct2/show/NCT02061436 (accessed 27 February 2021). 102. Galassi AR, Werner GS, Boukhris M, et al. Percutaneous recanalisation of chronic total occlusions: 2019 consensus document from the EuroCTO Club. EuroIntervention 2019;15:198–208. https://doi.org/10.4244/eij-d-18-00826; PMID: 30636678. 103. Brilakis ES, Grantham JA, Rinfret S, et al. A percutaneous treatment algorithm for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2012;5:367–79. https://doi. org/10.1016/j.jcin.2012.02.006; PMID: 22516392. 104. Li X, Liu Y, Gao J, et al. Comparison of graft vessel versus native vessel strategies for late saphenous vein graft disease after coronary artery bypass grafting. Zhonghua Xin Xue Guan Bing Za Zhi 2020;48:367–72 [in Chinese]. https:// doi.org/10.3760/cma.j.cn112148-0190827-00523; PMID: 32450652. 105. Lembo NJ, Karmpaliotis D, Kandzari DE. CTO PCI procedural planning. Interv Cardiol Clin 2012;1:299–308. https://doi. org/10.1016/j.iccl.2012.04.002; PMID: 28582014. 106. Bluemke DA, Achenbach S, Budoff M, et al. Noninvasive coronary artery imaging. Circulation 2008;118:586–606. https://doi.org/10.1161/circulationaha.108.189695; PMID: 18586979. 107. Opolski MP, Achenbach S, Schuhbäck A, et al. Coronary computed tomographic prediction rule for time-efficient guidewire crossing through chronic total occlusion insights from the CT-RECTOR Multicenter Registry (Computed Tomography Registry of Chronic Total Occlusion Revascularization). JACC Cardiovasc Interv 2015;8:257–67. https://doi.org/10.1016/j.jcin.2014.07.031; PMID: 25700748. 108. Tan Y, Zhou J, Zhang W, et al. Comparison of CT-RECTOR and J-CTO scores to predict chronic total occlusion difficulty for percutaneous coronary intervention. Int J Cardiol 2017;235:169–75. https://doi.org/10.1016/j.ijcard.2017.02.008; PMID: 28274578. 109. Malagutti P, Nieman K, Meijboom WB, et al. Use of 64-slice CT in symptomatic patients after coronary bypass surgery: evaluation of grafts and coronary arteries. Eur Heart J 2007;28:1879–85. https://doi.org/10.1093/eurheartj/ehl155; PMID: 16847009.

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Post-CABG Management of Occlusive CAD 110. Katsuragawa M, Fujiwara H, Miyamae M, et al. Histologic studies in percutaneous transluminal coronary angioplasty for chronic total occlusion: comparison of tapering and abrupt types of occlusion and short and long occluded segments. J Am Coll Cardiol 1993;21:604–11. https://doi. org/10.1016/0735-1097(93)90091-e; PMID: 8436741. 111. Asahi Intecc. http://www.asahi-intecc.co.jp/en/medical/pci/ gaia.html (accessed 30 April 2021). 112. Sapontis J, Marso SP, Lombardi WL, et al. How to fix common problems encountered in CTO PCI: the expanded hybrid approach. In: Rinfret S, ed. Percutaneous Intervention for Coronary Chronic Total Occlusion. Cham: Springer, 2016;141–59. https://doi.org/10.1007/978-3-319-21563-1_11. 113. Colombo A, Mikhail GW, Michev I, et al. Treating chronic total occlusions using subintimal tracking and reentry: the STAR technique. Catheter Cardiovasc Interv 2005;64:407–11. https://doi.org/10.1002/ccd.20307; PMID: 15789384. 114. Lombardi WL. Retrograde PCI: what will they think of next?

J Invasive Cardiol 2009;21:543; PMID: 19805844. 115. Valenti R, Vergara R, Migliorini A, et al. Predictors of reocclusion after successful drug-eluting stent-supported percutaneous coronary intervention of chronic total occlusion. J Am Coll Cardiol 2013;61:545–50. https://doi. org/10.1016/j.jacc.2012.10.036; PMID: 23273395. 116. Azzalini L, Poletti E, Ayoub M, et al. Coronary artery perforation during chronic total occlusion percutaneous coronary intervention: epidemiology, mechanisms, management, and outcomes. EuroIntervention 2019;15:e804– 11. https://doi.org/10.4244/eij-d-19-00282; PMID: 31217142. 117. Matsuno S, Tsuchikane E, Harding SA, et al. Overview and proposed terminology for the reverse controlled antegrade and retrograde tracking (reverse CART) techniques. EuroIntervention 2018;14:94–101. https://doi.org/10.4244/eij-d17-00867; PMID: 29360064. 118. Brinkmann C, Eitan A, Schwencke C, et al. Rotational atherectomy in CTO lesions: too risky? Outcome of

rotational atherectomy in CTO lesions compared to non-CTO lesions. EuroIntervention 2018;14:e1192–8. https://doi. org/10.4244/eij-d-18-00393; PMID: 30175961. 119. Yeoh J, Hill J, Spratt JC. Intravascular lithotripsy assisted chronic total occlusion revascularization with reverse controlled antegrade retrograde tracking. Catheter Cardiovasc Interv 2019;93:1295–7. https://doi.org/10.1002/ ccd.28165; PMID: 30838746. 120. del Olmo VV, Rodríguez-Leor O, Redondo A, et al. Intracoronary lithotripsy in a high-risk real-world population. First experience in severely calcified, complex coronary lesions. REC Interv Cardiol 2020;2:76–81. https://doi. org/10.24875/RECICE.M19000083. 121. Wilson SJ, Hanratty CG, Spence MS, et al. Saphenous vein graft sacrifice following native vessel PCI is safe and associated with favourable longer-term outcomes. Cardiovasc Revasc Med 2019;20:1048–52. https://doi. org/10.1016/j.carrev.2019.01.025; PMID: 30745059.

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Expert Opinion

Invasive Haemodynamic Assessment Before and After Left Ventricular Assist Device Implantation: A Guide to Current Practice Jesus Gonzalez and Paul Callan Wythenshawe Cardiothoracic Transplant Unit, Manchester Foundation Trust, Wythenshawe Hospital, Wythenshawe, Manchester, UK

Abstract

Mechanical circulatory support for the management of advanced heart failure is a rapidly evolving field. The number of durable long-term left ventricular assist device (LVAD) implantations increases each year, either as a bridge to heart transplantation or as a stand-alone ‘destination therapy’ to improve quantity and quality of life for people with end-stage heart failure. Advances in cardiac imaging and non-invasive assessment of cardiac function have resulted in a diminished role for right heart catheterisation (RHC) in general cardiology practice; however, it remains an essential tool in the evaluation of potential LVAD recipients, and in their long-term management. In this review, the authors discuss practical aspects of performing RHC and potential complications. They describe the haemodynamic markers associated with a poor prognosis in patients with left ventricular systolic dysfunction and evaluate the measures of right ventricular (RV) function that predict risk of RV failure following LVAD implantation. They also discuss the value of RHC in the perioperative period; when monitoring for longer term complications; and in the assessment of potential left ventricular recovery.

Keywords

Left ventricular assist devices, heart failure, right heart catheterisation, mechanical circulatory support, pulmonary hypertension, perioperative care, heart transplantation Disclosure: PC has received consulting fees, honoraria for presentations and support for attending meetings from Medtronic, and support for attending meetings and travel from Abbott. JG has no conflicts of interest to declare. Received: 29 March 2021 Accepted: 10 October 2021 Citation: Interventional Cardiology 2021;16:e34. DOI: https://doi.org/10.15420/icr.2021.13 Correspondence: Jesus Gonzalez, Wythenshawe Cardiothoracic Transplant Unit Manchester Foundation Trust, Wythenshawe Hospital, Southmoor Rd, Wythenshawe, Manchester M23 9LT, UK. E: jealgole@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

End-stage heart failure (HF) accounts for a large proportion of deaths in developed countries and the gold standard treatment is orthotopic heart transplantation. Due to the growing population of patients with advanced HF and the ongoing shortage of available organs, mechanical circulatory support (MCS) with long-term left ventricular assist devices (LVADs) has become a common treatment for patients with severe left ventricular systolic dysfunction who no longer respond to optimal medical therapy (OMT). LVAD therapy improves outcomes in HF patients by unloading the left ventricle (LV), increasing cardiac output and lowering intracardiac pressures. As a result, LVADs enhance peripheral circulation and maintain end-organ perfusion, improve functional capacity and relieve HF symptoms.1 MCS has been historically used to ensure the survival of patients with endstage HF until a donor organ becomes available, a strategy referred as a bridge to transplantation (BTT). Several studies have demonstrated that LVADs when used as a BTT reduce mortality by improving the patient´s overall condition before heart transplantation and also improving posttransplant survival.2–5 Furthermore, BTT strategy represents an especially effective alternative for patients with advanced HF who are young, have renal dysfunction or expect prolonged waiting times.6 LVAD implantation as a BTT also improves the quality of life of patients with end-stage HF by allowing them to leave hospital while waiting for heart transplantation.

A growing number of patients in some countries have received LVADs as a permanent treatment or ‘destination therapy’ (DT) since the publication of the REMATCH trial in 2001. REMATCH demonstrated improved survival in patients with advanced HF who are ineligible for heart transplantation who were treated with LVADs versus OMT. Another group of patients who may potentially benefit are those with comorbidities that represent relative contraindications to heart transplantation and may be reversible after a period of mechanical haemodynamic support; a strategy known as a bridge to decision (BTD).7 Furthermore, a very small proportion of LVAD patients have underlying causes of systolic dysfunction that may be reversible over time and they may recover sufficient cardiac function to allow withdrawal of MCS.8 According to the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database, between 2008 and 2017, 26% of patients with LVADs were listed for cardiac transplantation at the time of LVAD implant (BTT), 43% as DT, 30% as BTD and less than 1% of LVADs were explanted after sufficient recovery of LV systolic function.9 Most patients treated with implantable LVADs receive an intracorporeal rotary pump that unloads the failing LV continuously by pumping blood to the ascending aorta, either an axial flow pump such as the HeartMate II (HM2; Abbott), a centrifugal pump such as the HeartWare HVAD (Medtronic) or the new generation magnetically levitated centrifugal

Haemodynamic Assessment Before and After LVAD Implant Figure 1: Basic Left Ventricular Assist Device Components 1

HeartMate 3 LVAD

System Controller

Batteries

Modular Driveline

3 Driveline exits abdomen close to umbilicus

Components 2, 3 and 4 are external to the body

The inflow cannula is surgically implanted into the left ventricular apex, conducting blood from the left ventricle to the pump (1), which houses an impeller that impulses the blood into the systemic circulation through an outflow graft inserted in the aorta. The dual set of external batteries (3) provides power to an external controller (2) that operates and monitors the pump function. A surgically tunnelled driveline (4) connects the pump to the system controller (2). Source: Abbott Laboratories.92 Reproduced with permission from Abbott Laboratories.

pump HeartMate III (HM3; Abbott). In June 2021, Medtronic stopped distribution and sale of the HeartWare HVAD, meaning that the HM3 device is currently the sole durable LVAD available for new implants. Regardless of their design, all have the components shown in Figure 1: an inflow cannula surgically implanted into the LV apex conducting blood from the LV to the pump, which houses an impeller that impulses the blood into the systemic circulation through an outflow graft inserted in the aorta; a dual set of external batteries that provide power to an external controller that operates and monitors the pump function; and a surgically tunnelled driveline that connects the pump to the system controller. The pumps generate up to 10 l/min of flow, which is calculated based on measured pump power and set pump speed.10 Right heart catheterisation (RHC) is a key investigation in the assessment of patients being considered for LVAD implantation and heart transplantation. Haemodynamic evaluation using RHC remains the gold standard to providing objective metrics of right ventricle (RV) function, pulmonary pressures and cardiac output. This review outlines the use of RHC prior to LVAD implantation for prognostic assessment in the perioperative period, when evaluating postoperative complications, and when assessing for bridge to recovery.

Overview of Right Heart Catheterisation

RHC plays a significant role in the prognostic evaluation and decisionmaking for patients with end-stage HF. The route of access depends on several factors, including operator expertise, the presence of cardiac devices, previous history of venous cannulation and associated complications.11 Femoral vein access is commonly used if left heart catheterisation is jointly performed, although some studies have demonstrated the safety of performing RHC and left heart catheterisation

via the antecubital fossa vein and radial artery.12–14 A meta-analysis comparing landmark-based versus ultrasound-guided venous access demonstrated a clear beneﬁt of ultrasound for internal jugular vein (IJV) cannulation, with a higher success rate and fewer complications.15 RHC can be performed without interrupting anticoagulation in patients undergoing RHC via either IJV or antecubital veins with an international normalised ratio (INR) <3.5.16 Complications associated with RHC are uncommon in modern clinical practice; however, when they do occur the consequences can be severe and sometimes fatal. Case reports or case series are the main source of reported complications, and they can be categorised as related to either vascular access or the catheterisation procedure itself. The most frequent injuries related to access are carotid artery injury and the formation of arteriovenous fistula. Other access site-related complications include pseudoaneurysm of the common femoral vein, perforation of the right innominate vein, deep venous thrombosis, perforation of the left internal mammary and right lymphatic duct injury. Access-site complications can be significantly reduced by performing ultrasound-guided vessel puncture. The most reported catheter-related complication is injury to the tricuspid valve. Pulmonary artery (PA) rupture carries a high mortality rate in the reported literature; however, it occurs in less than 0.5% of cases. Other catheter-related complications include catheter knotting or bending, right atrial (RA) perforation and severe cardiac arrythmias.17

Right Heart Catheterisation Prior to LVAD Implantation

RHC in a patient being evaluated for advanced HF therapies should help to answer the following questions (Table 1):

• Do the cardiac haemodynamics indicate a poor prognosis, thus suggesting a potential benefit from transplantation or MCS?

• Are the pulmonary pressures low enough to enable safe transplantation?

• If LVAD therapy is being considered, what is the risk of postimplantation RV failure?

Haemodynamics as a Prognostic Indicator in End-stage Heart Failure

RHC remains an important test for assessing the need for MCS as well as maintaining candidacy for heart transplantation. As per the International Society for Heart and Lung Transplantation (ISHLT), RHC remains a class 1 recommendation for all candidates before being listed for heart transplantation and it should be performed annually until transplantation.18 Several studies have highlighted the role of clinical and haemodynamic profiling of patients with HF in predicting the risk of clinical deterioration and short-term survival.19,20 Four haemodynamic profiles have been characterised defined by the presence or absence of pulmonary venous congestion (pulmonary capillary wedge pressure [PCWP] >15 mmHg or PCWP <15 mmHg) and adequacy of perfusion (cardiac index >2.2 l/min/m2):

• • • •

Profile I: no congestion or hypoperfusion; Profile II: congestion without hypoperfusion; Profile III: hypoperfusion without congestion; and Profile IV: both congestion and hypoperfusion.

Several clinical features can accurately predict haemodynamic derangements in HF. Orthopnea and a New York Heart Association (NYHA) class III/IV correlate with elevated PCWP, renal dysfunction with

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Haemodynamic Assessment Before and After LVAD Implant Table 1: Dataset for Haemodynamic Evaluation Prior to Consideration for Left Ventricular Assist Device Implantation Measurement

Normal Value

Comment

Right atrial pressure

0–5 mmHg

RAP >15 mmHg associated with increased risk of RV failure post-implant

Pulmonary artery pressure

Systolic 15–25 mmHg Elevated PAP prognostic marker in advanced heart failure Mean 8–16 mmHg Systolic PA >60 mmHg associated with increased risk of primary graft dysfunction post-transplant

Pulmonary capillary wedge pressure

6–12 mmHg

Elevated PCWP prognostic marker in advanced heart failure

Cardiac output

4–8 l/min

Measured using Fick or thermodilution methods

Cardiac index

2.5–4 l/min/m2

Prognostic marker in heart failure Cardiac index <2 l/min/m2 one of the UK’s transplant listing criteria

Transpulmonary gradient (mean PAP − mean PCWP)

<12 mmHg

TPG >15 mmHg contraindication to transplant

Pulmonary vascular resistance (TPG/cardiac output)

<3 WU

PVR >5 WU contraindication to transplant

RV Stroke Work Index (mean PAP − RAP) × CI × 0.0136/heart rate

>400 mmHg/ml/m2

Low RVSWI associated with increased risk of RV failure post LVAD implant

RA:PCWP ratio

>0.63

Low RA:PCWP associated with increased risk of RV failure post-LVAD implant

Pulmonary artery Pulsatility Index (systolic PAP − diastolic PAP)/central venous pressure

PAPi <1.85 associated with increased risk of RV failure post LVAD implant

CO = cardiac output; CI = cardiac index; LVAD = left ventricular assist device; PA = pulmonary artery; PAP = pulmonary artery pressure; PAPi = pulmonary artery pulsatility index; PCWP = pulmonary capillary wedge pressure; RAP = right atrial pressure; RV = right ventricle; RVSWI = RV stroke work index; TPG = transpulmonary gradient; WU = Wood units.

elevated RA pressure, and hepatic dysfunction with increased PCWP and RA pressure. Patients with pulmonary venous congestion, elevated RA pressure and low cardiac output have been identified as the group with the highest risk of death or clinical deterioration.21–23 Identification of this cohort of patients with poor prognostic markers is essential to evaluate the potential benefit of heart transplantation or LVAD therapy.

Pulmonary Pressures Assessment in Advanced Heart Failure

Progression of HF alters the pulmonary circulation as a consequence of chronically elevated left atrial and post-capillary pressures, leading to changes in the pulmonary vasculature that over time become irreversible. Pulmonary vasoconstriction and vascular remodeling ultimately lead to fixed pulmonary hypertension (PH). Elevated PA pressure and pulmonary vascular resistance (PVR) in the transplant recipient are associated with an increased risk of failure of the non-conditioned donor RV following transplantation, which leads to signiﬁcant morbidity and mortality in the early post-operative period. ISHLT considers a PVR >5 Wood units and trans-pulmonary gradient (TPG) >15 mmHg as contraindications to transplantation.24–26 LVAD implantation in type 2 PH frequently leads to significant reductions in TPG and PVR and this is attributed to the LVAD´s ability to mechanically unload the LV and subsequently reduce left-sided filling pressures (Figure 2).27–31 Therefore, LVAD implantation offers an opportunity for patients with advanced HF and type 2 PH without other comorbidities to become eligible for heart transplantation.

Assessing the Risk of Right Ventricular Failure Post-LVAD Implantation

Due to the increasing patient population eligible for long-term mechanical support, RV failure post-LVAD implantation has become more commonly encountered in clinical practice. Therefore, assessment of RV haemodynamics is particularly important before LVAD placement.32 Given that LVADs only support the LV, RV function needs to be sufficient to overcome the PVR to adequately fill the LV and therefore maintain systemic circulation. RV function may be impaired due to a cardiomyopathic process or coronary artery disease and needs to be able to tolerate the increased

preload stress from additional LVAD flows and also maintain contractility. Several predictors of post-LVAD RV failure have been identified but there is no consensus on which measures of RV function would constitute an absolute contraindication for LVAD implantation.33–36 As a result, accurate preoperative prediction of RV failure post-LVAD implant remains a significant challenge. One of the main risk factors for post-operative RV failure is preoperative RV dysfunction. However, RV function can improve post-LVAD implantation as a result of decongestion of the LV, lowering filling pressures and reducing pulmonary pressures.37 Assessment of the risk of RV failure post-LVAD implantation should be evaluated not only through haemodynamic and echocardiographic variables, but also by taking into account additional clinical factors. The most consistent preoperative factors associated with the development of RV failure include the need for mechanical ventilation or renal replacement therapy.38 Additionally, patients with more severe HF, as measured by the INTERMACS score, are at greater risk of RV failure.39 LVAD device type does not appear to influence risk of RV failure, with similar rates seen between axial and centrifugal flow pumps in the MOMENTUM study.40 Specific echocardiographic predictors of RV dysfunction have exhibited poor reproducibility across studies and should not be taken solely into consideration when addressing LVAD implantation. Puwanant et al. reported that a tricuspid annular plane systolic excursion <7.5 mm provided a specificity of 0.9 and a sensitivity of 0.46 for prediction of RV failure, whereas Kukucka et al. reported that an RV-to-LV end-diastolic diameter ratio >0.72 by transoesophageal echocardiography showed a sensitivity of 0.80 and specificity of 0.74 for RV failure after LVAD placement.41,42 Haemodynamic parameters identified as potential RV failure predictors in single-centre studies include a low RV stroke work index (RVSWI) and a RA to pulmonary capillary wedge ratio (RA:PCWR) greater than 0.63.43,44 PA pulsatility index (PAPi) is the difference between the PA systolic and diastolic pressures, divided by the central venous pressure. A PAPi <1.85 was identified as the optimal cut-off to determine an increased risk of early RV failure.45 A more recent study by Gonzalez et al. assessed the use of

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Haemodynamic Assessment Before and After LVAD Implant Figure 2: Pulmonary Artery and Pulmonary Capillary Wedge Pressure Traces from a Patient with Ischaemic Cardiomyopathy A

100

90 80

45 81

Pre implant Cardiac output 2.46 l/min Transpulmonary gradient 20 mmHg Pulmonary vascular resistance 8.13 Wood units

5 Post implant Cardiac output 5.5 l/min Transpulmonary gradient 6 mmHg Pulmonary vascular resistance 1.1 Wood units

D 40

B 70

27 22

39 31

36 28

25 28

34 29

20 15

14 14

14 12 7

*A,B: prior to HM3 LVAD implantation; C,D: 6 months after HM3 LVAD implantation.

serial testing, by combining an initial PAPi with one following optimisation with diuresis and inotropes.46 A low combined PAPi was independently associated with higher risk of early RV failure, highlighting the value of determining RV contractile reserve through dynamic assessment. RV prediction scores have been developed combining multiple preoperative variables. One of the first algorithms was the Michigan RV failure risk score, which incorporated perioperative variables like vasopressor requirement, renal dysfunction and elevated bilirubin levels.47 A more contemporary risk score was developed by Kormos et al. using the Heartmate II BTT data, and found that a CVP:PCWP >0.63, a blood urea nitrogen greater than 39 mg/dl, or the need for preoperative ventilatory support were associated with RV failure.48 The EUROMACS score, which incorporates five clinical variables, includes one haemodynamic measure – RA:PCWP ratio.39 The c-statistic of 0.7 in the development cohort was better than other prediction tools, however it performed less well in small-to-moderately sized single-centre external validation cohorts.49,50 This has also been the case for validation of other risk prediction tools, which have demonstrated modest-to-poor discriminatory ability in external populations.

Haemodynamics Following LVAD Implantation

In general intensive care practice, the use of PA catheters has declined over recent decades. Nevertheless, in cardiac surgery PA catheters are still commonly placed to facilitate perioperative management. Following LVAD implantation, the continuous LV unloading produces a drastic reduction on PCWP and mean PA pressure and an increase in cardiac output. The reduction of RV afterload improves the RVSWI and tricuspid

regurgitation. Furthermore, Goodwin et al. demonstrated that LVAD implantation frequently corrects functional mitral regurgitation without any concomitant perioperative mitral valve intervention.51 Comparison of haemodynamics among different devices is difficult as haemodynamics are also dependent on each centre’s perioperative management protocol and every patient’s previous condition. Haemodynamic assessment in the early post-operative period can also facilitate the diagnosis of potential life-threatening complications, including acute RV failure and cardiac tamponade secondary to postprocedure pericardial bleeding or localised haematoma.

Acute Right Ventricular Failure

Acute RV failure in the early post-operative period may develop in patients after LVAD implantation. This is characterised by elevated central venous pressure (CVP), RA and PA pressures with reduced LVAD flows and cardiac output requiring RV support (inotropic or mechanical) for more than 14 days post-LVAD surgery. Severe RV failure after LVAD implantation is associated with an important increase in morbidity and mortality and less successful bridging to cardiac transplantation.33,48–50,52–54 The incidence of post-operative RV failure ranges from 5% to 44%, in part due to the varying definitions of RV failure in this patient population.55 Early perioperative RV failure has been most consistently defined according to the INTERMACS database by documentation of elevated CVP by either RHC (CVP or RA pressure >16 mmHg) or echocardiographic findings of a significantly dilated inferior vena cava with absence of inspiratory variation alongside clinical features such as jugular venous distension,

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Haemodynamic Assessment Before and After LVAD Implant peripheral oedema, presence of ascites or laboratory evidence of hepatic and/or renal dysfunction (total bilirubin >2.0 mg/dl, creatinine >2.0 mg/dl). Furthermore, RV failure is characterised as mild, moderate or severe predominantly based on signs of elevated CVP, duration of inotropic/ vasodilator support, the need for temporary right-sided mechanical support device (RVAD) implantation or death from RV failure.56 Perioperative factors that influence the development of RV failure in the early post-operative period include cardioplegia during cardiopulmonary bypass, which can lead to myocardial stunning and inadequate RV unloading. Systemic inflammatory response and acute hypoxaemia during surgery can result in pulmonary vasoconstriction, PVR elevation and poor RV adaptation. While LVAD flows typically drop with acute RV failure due to reduced LV filling, filling can be maintained in some patients at the expense of high RV preload, leading to hepatic and renal congestion. Following LVAD implantation, increased LV unloading results in increased venous return and RV preload which may increase RV wall stress. In addition, the loss of septal contribution to RV function can result in worsening RV dimensions and tricuspid regurgitation.57,58 These pathophysiological mechanisms may also contribute to the development of late RV failure. Preoperative management for prevention of RV failure include optimisation of preload, afterload and contractility. CVP should be maintained below 15 mmHg using diuretics and inotropes such as milrinone and dopamine can be used to optimise cardiac output and improve systemic and pulmonary vascular resistance through their vasodilatory effects. Temporary mechanical support devices may be used in patients who remain haemodynamically compromised, and consideration of bridging with venoarterial extracorporeal membrane oxygenation should be assessed in patients with critical cardiogenic shock to stabilise haemodynamics and improve end-organ perfusion prior to LVAD implantation.33 When early post-operative RV failure occurs, consideration of early use of RVAD should be made to preserve LV filling and end-organ perfusion. Several studies have showed that planned or early RVAD implantation is associated with better outcomes versus delayed or rescue RVAD placement.59,60

Cardiac Tamponade

Cardiac tamponade after cardiac surgery is a medical emergency that can be reversed with accurate recognition. This complication occurs due to an abnormal accumulation of fluid in the pericardial sac, producing an increase in intrapericardial pressure that impedes normal intracardiac filling. Subsequently, the reduction of cardiac output and LVAD flows will result in a reduction of systemic perfusion, producing hypotension, tachycardia and peripheral vasoconstriction. Although clinical and echocardiographic examination are central components of diagnosis, several studies have illustrated the atypical presentation of cardiac tamponade following cardiac surgery, where conventional signs may be absent and localised collections (usually blood, serous fluid and, sometimes, infective material) may be incorrectly visualised.61 In this setting, invasive haemodynamic assessment can provide further evidence to support the diagnosis of this complication, as well excluding other causes of shock. The elevation of intrapericardial pressure will transmit to all cardiac chambers, especially affecting the early diastolic phase and subsequently producing equalisation of all cardiac and PA diastolic pressures. An increase in RA pressure will reduce the veno-atrial gradients that determine the cardiac output. In addition, the RA is the chamber most vulnerable to compression because it has the least intracavity pressure. During inspiration, the increase in venous return and right-side filling will

produce a subsequent rise in RA pressure and an opposite decrease in the left chambers filling.62,63 In the setting of low cardiac output and decreased LVAD flows, the combination of elevated right-side pressures and diastolic equalisation of RA, RV, PA and PCWP pressures should point towards the possibility of cardiac tamponade, and goal-directed bedside echocardiography should be performed. It should be noted that the classic haemodynamic findings of cardiac tamponade may not be present when the parietal pericardium is not intact; patients sometimes have localised haemorrhage/haematoma that causes right-sided chamber compression, and the haemodynamics are often atypical in that setting. Hence, a multimodal approach is necessary. Pericardiocentesis may be considered the initial therapeutic measure in this setting because repeated median sternotomy could increase the risk of mediastinitis.64

Implications of Right Heart Catheterisation in the Post-operative Period

LVADs have a positive effect in reducing PA pressures by continuously unloading the LV. ISHLT guidelines recommend serial invasive haemodynamic assessment to survey PH in patients with LVADs as a BTT strategy.65 Routine RHC is recommended 3 to 6 months after LVAD implantation to demonstrate normalisation of PA pressures and therefore allow the patient to be listed for heart transplantation. However, the ideal surveillance frequency is unknown for patients without PH prior to LVAD implantation or for those whose PA pressures and PVR have normalised post-LVAD implantation. Recent publications suggest that routine RHC may not be necessary for asymptomatic patients with normal PVR pre-LVAD implant or PVR <2.5 6 months post-LVAD implantation.66,67 Haemodynamic reassessment in LVAD patients is indicated regardless of previous measurements in the presence of new onset HF symptoms, or complications like significant aortic regurgitation or late RV failure. Non-invasive echocardiographic estimates of cardiac filling pressures in LVAD recipients have demonstrated a good correlation with right heart catheter measurements. LA volume index, mitral inflow velocities, PA systolic estimates using TR velocity, and an RA pressure estimate using the inferior vena cava can be combined in an algorithm to identify patients with elevated pulmonary capillary wedge pressures.68 However, echocardiographic assessment can be challenging due to the presence of the apically placed VAD pump, and the four measures listed above could not be obtained in about one-quarter of patients. There is growing interest in the use of implantable haemodynamic monitoring systems, such as the CardioMEMS system (Abbott) and Titan LAP monitoring system (ISS Inc) that allow remote monitoring of HF patients.69,70 Real-time haemodynamic monitoring of LVAD recipients may allow more efficient device optimisation and detection of complications. The ongoing HEMOVAD study seeks to address its use in this setting.71 ISHLT guidelines recommend echocardiographic assessment post-LVAD implantation as an integral way to determine optimal LVAD speed, with goals including adequate LV unloading with midline LV septum and minimal mitral valve regurgitation.63 Haemodynamic assessment for LVAD speed optimisation may provide additional benefits above non-invasive evaluation alone. A combined haemodynamic and echocardiographic ramp study was described by Uriel et al.72 A baseline RHC was performed, then the device speeds were lowered to 2,300 rpm for HVAD recipients and 8,000 rpm for HM2 recipients, The speed was increased in 100 rpm and 400 rpm increments to a maximum of 3,200 rpm and 12,000 rpm, respectively. Complete pressure assessment and cardiac output via the indirect Fick method were measured at each speed, following a 2-minute period of stabilisation. Speed increases were stopped in the event of

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Haemodynamic Assessment Before and After LVAD Implant Table 2: Typical Haemodynamic Profiles Associated with Ventricular Assist Device-related Complications Complication

RA Pressure PA Pressure PCWP Cardiac Output

Right ventricular failure

↑↑

↓

↓ or ←→ ↓

Cardiac tamponade ↑↑

↑ or ←→

↑

↓

Aortic regurgitation ←→

↑

↓

Pump thrombosis

↑

↑↑

↓↓

↑ or ←→

↑ = increased; ↑↑ = significantly increased; ↓ = decreased; ↓↓ = significantly decreased; ←→ unchanged; RA = right atrial; PA = pulmonary artery; PCWP = pulmonary capillary wedge pressure.

Table 3: Manchester Recovery Criteria Investigation

Required Criteria

Mean arterial pressure

>65 mmHg

Echocardiogram

LV ejection fraction >50% LV end diastolic diameter <55 mm

Cardiopulmonary exercise test

Peak VO2 >20 ml/kg/min VE/VCO2 slope <30

Right heart catheter

Cardiac Index 2.4 l/min/m2 Pulmonary capillary wedge pressure <12 mmHg

All investigations were performed after left ventricular assist device was set at nominal VAD speed for 15 minutes. LV = left ventricle; VE = ventilation.

suction events or an LV end-diastolic diameter of <3 cm. The goal was to achieve PCWP <18 mmHg and CVP <12 mmHg with minimal residual mitral regurgitation and intermittent valve opening. In a subsequent multicentre pilot study, the addition of serial haemodynamic ramp studies when compared to standard echocardiographic assessment alone was associated with a greater number of speed modifications and a numerical reduction in adverse event rates.73 This supports the development of a fully powered trial to assess the impact of haemodynamic optimisation on long-term patient outcomes.

Monitoring for LVAD Complications

Third generation LVADs such as the HeartMate III have demonstrated lower rates of pump thrombosis, pump failure and stroke compared to the second-generation Heartmate II device.40 However, there are other long-term complications that can lead to serious adverse outcomes and periodic RHC plays an important role in their diagnosis and risk stratification (Table 2).

Late Right Ventricular Failure

INTERMACS define late RV failure as new RV failure occurring at least 3 months post-VAD implant, characterised by evidence of raised CVP, signs and symptoms of fluid retention, such as peripheral oedema and ascites, and/or evidence of worsening hepatic or renal function. Severity is defined according to the need for readmission for intravenous diuretics and vasodilators, inotrope therapy or RVAD implant.52 Late RV failure can occur as a consequence of inadequate unloading from the LVAD due to severe aortic or mitral regurgitation, mechanical LVAD dysfunction or inadequate blood pressure management. However, in other patients late RV failure occurs in the context of normal LVAD function as a result of intrinsic RV disease.32 Regardless of the underlying cause, several studies have showed the impact of this complication as a predictor of poorer long-term outcomes during LVAD support and even after heart transplantation.74–77

Haemodynamic findings concordant with late RV failure include elevated CVP and RA pressure, equalisation of right sided pressures, low cardiac output and LVAD flows as a consequence of poor LV filling. The adequate management of this clinical scenario remains a big challenge. Pump speed optimisation by haemodynamic or echocardiographic assessment can lead to an improvement of RV function and preload optimisation using diuretics may provide a short-term amelioration of symptoms. Nevertheless, in patients with LVADs as a BTT, late RV failure may be an ominous sign that there is an urgent need for heart transplantation.

Aortic Regurgitation

Aortic regurgitation (AR) affects 25–30% of patients within the first year following LVAD implantation. Significant AR can create a continuous closedloop circuit that leads to suboptimal LV unloading, inadequate peripheral perfusion and recurrent symptoms of HF. This phenomenon leads to an inaccurate estimation of the amount of litres per minute unloaded from the LV into the systemic circulation, producing a discrepancy between the cardiac output measured during RHC and the LVAD-derived flows. With AR progression, LV dimensions, end-diastolic pressure and mitral regurgitation will increase for a given pump speed, increasing the PCWP and PA pressures, which can subsequently lead to RV failure. In addition, AR increases aortic wall stress and has been associated with haemolysis and pump thrombosis. Nevertheless, it is unproven whether AR has an independent impact on prognosis.78,79 The main factors associated with the development and worsening of AR are a persistently closed aortic valve and prolonged duration of LVAD support. The underlying mechanisms of this alteration of the aortic root biomechanics include repetitive microtrauma of the valvular endothelium and consequently commissural fusion, tissue remodelling and ultimately valvular incompetence.80–82 Other risk factors associated with the development of AR include small body surface area, older age and being female. It is important to assess the aortic valve prior to LVAD implantation, and a concomitant procedure should be performed in the presence of at least moderate AR.83 There is no clear recommendation regarding the management of patients who develop AR under LVAD support. Targeting the lowest pump speed that allows intermittent aortic valve opening is in theory indicated to reduce AR progression, although this puts patients at risk of a low-output state and thrombotic events. In symptomatic patients, in addition to lowering LVAD pump speeds, medical therapy using vasodilators and diuretics is indicated to reduce LV afterload and aortic wall stress.79,82 Surgical correction should be considered for patients with at least moderate AR and symptoms despite OMT and device optimisation.83 Surgical alternatives include aortic valve repair, replacement or closure. Case series providing long-term outcomes data are scarce and perioperative mortality is considerable.84 In symptomatic patients with excessive surgical risk, percutaneous options may be considered, using either percutaneous occlusion devices (PODs) or transcatheter aortic valve implantation (TAVI). However, results on case series reports paint a bleak picture. In 10 patients treated with PODs, Retzer et al. reported a 70% in-hospital mortality, mainly attributable to RV failure.85 Another report on 29 LVAD patients with symptomatic AR who underwent percutaneous repair (8 TAVI and 21 PODs), showed similar benefit for AR reduction from severe to trivial, but with 31% peri-procedural mortality and an additional 25% mortality at 1 year.86

Pump Thrombosis

LVAD pump thrombosis is a life-threatening complication that requires prompt recognition and treatment. Thrombosis rates have reduced significantly with

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Haemodynamic Assessment Before and After LVAD Implant the introduction of the HM3 pump, as demonstrated in the MOMENTUM 3 trial (1% pump thrombosis rate after 24 months in the HM3 arm versus 14% in the HM2 arm.40 Clinical indicators of pump thrombosis include:

• Abrupt onset of HF symptoms, with signs of pulmonary oedema and low cardiac output.

• A sudden increase in power consumption on device interrogation. • Signs of haemolysis – elevated lactate dehydrogenase (levels >1,000 IU/l highly suggestive of pump thrombus), bilirubinuria, elevated plasma-free haemoglobin. • Echocardiographic signs of ineffective LV unloading – LV dilation, increased frequency of aortic valve opening, worsening mitral regurgitation or pulmonary hypertension. • Negative ramp study using echocardiogram – increasing pump speed has no effect on LV unloading.

RHC is rarely required, but in cases where the diagnosis is less clear, for example modest power and lactate dehydrogenase rises, or in patients with poor echocardiographic windows, haemodynamic evaluation can be useful to look for evidence of the adequacy of LV unloading. LVAD flows are derived based on power consumption and speed, therefore in the presence of thrombus, an increase in pump power will result in falsely high flow estimates. Direct measurement of cardiac output via Fick or thermodilution methods will therefore provide a much more reliable estimate. Other indicators of pump thrombosis include an elevation in PA and PCW pressures. Pump exchange is usually required in confirmed pump thrombosis, but in patients who are considered too unwell for repeat surgery, treatment with heparin, glycoprotein IIb/IIIa inhibitors, direct thrombin inhibitors or thrombolytics can be considered.87,88 Continuous haemodynamic monitoring with a PA catheter to assess cardiac output and PA pressures can be useful to assess treatment response.

The Role of Right Heart Catheterisation on Myocardial Recovery Assessment

The incidence of myocardial recovery under MCS with LVADs is variable, as are the rates of relapse into HF after device explant. INTERMACS is 1. Imamura T, Chung B, Nguyen A, et al. Clinical implications of haemodynamic assessment during left ventricular assist device therapy. J Cardiol 2018;71:352–8. https://doi. org/10.1016/j.jjcc.2017.12.001; PMID: 29287808. 2. Patel S, Nicholson L, Cassidy CJ, et al. Left ventricular assist device: a bridge to transplant or destination therapy? Postgrad Med J 2016;92:271–81. https://doi.org/10.1136/ postgradmedj-2015-133718; PMID: 26969730. 3. Slaughter MS, Singh R. The role of ventricular assist devices in advanced heart failure. Rev Esp Cardiol (Engl Ed) 2012;65:982–5. https://doi.org/10.1016/j.recesp.2012.02.030; PMID: 23026124. 4. Kamdar F, John R, Eckman P, et al. Postcardiac transplant survival in the current era in patients receiving continuousflow left ventricular assist devices. J Thorac Cardiovasc Surg 2013;145:575–81. https://doi.org/10.1016/j.jtcvs.2012.09.095; PMID: 23321132. 5. Slaughter MS, Pagani FD, McGee EC, et al. HeartWare ventricular assist system for bridge to transplant: combined results of the bridge to transplant and continued access protocol trial. J Heart Lung Transplant 2013;32:675–83. https://doi.org/10.1016/j.healun.2013.04.004; PMID: 23796152. 6. Seco M, Zhao DF, Byrom MJ, et al. Long-term prognosis and cost-effectiveness of left ventricular assist device as bridge to transplantation: a systematic review. Int J Cardiol 2017;235:22–32. https://doi.org/10.1016/j.ijcard.2017.02.137; PMID: 28285802. 7. Gustafsson F, Rogers JG. Left ventricular assist device therapy in advanced heart failure: patient selection and outcomes. Eur J Heart Fail 2017;19:595–602. https://doi. org/10.1002/ejhf.779; PMID: 28198133. 8. Chaggar PS, Williams SG, Yonan N, et al. Myocardial

10. 11. 12.

13.

14.

15.

the largest published database of durable MCS implants and reports a recovery rate of 0.9 to 1.3%.8,9 Identifying LVAD patients who experience myocardial recovery is based on assessing clinical, haemodynamic and echocardiographic parameters. Likely indicators of LV recovery in asymptomatic LVAD patients include echocardiographic variables, such as normalisation of ejection fraction and LV dimensions as well as improvement of haemodynamic parameters that are sustained on pump speed reduction. Cardiopulmonary exercise testing is also employed as an objective measure of exercise capacity and a prognostic indicator. RHC for recovery assessment is performed while patients are anticoagulated with warfarin and have therapeutic INR, and they are given a bolus of intravenous heparin immediately prior to reducing the VAD speed, given the increased risk of stasis and thrombus formation. The Manchester recovery protocol requires a number of criteria to be met after 15 minutes of minimal LVAD flow before considering LVAD explant (Table 3). These variables are based on a combination of parameters from the Harefield and Berlin criteria, which represent the two European centres with the greatest experience of LVAD explant for recovery.89–91 In our centre, explant criteria were developed based on the above studies, and to date eight successful LVAD explants have been performed with no deaths or need for transplantation in the first 2 years of follow-up.89–91

Conclusion

Invasive haemodynamic assessment plays a vital role for clinicians involved in the implantation and management of patients with durable LVADs. It informs patient selection, helps to stratify perioperative risk, and can be useful in the recognition and evaluation of both short- and long-term LVAD-related complications. Larger studies are required to determine the optimal haemodynamic measures that predict risk of RV dysfunction post-LVAD implant, as well as markers of myocardial recovery that permit safe explantation of the device.

recovery with mechanical circulatory support. Eur J Heart Fail 2016;18:1220–7. https://doi.org/10.1002/ejhf.575; PMID: 27297263. Kormos RL, Cowger J, Pagani FD, et al. The Society of Thoracic Surgeons INTERMACS database annual report: evolving indications, outcomes, and scientific partnerships. J Heart Lung Transplant 2019;38:114–26. https://doi. org/10.1016/j.healun.2018.11.013; PMID: 30691593. Aissaoui N, Jouan J, Gourjault M, et al. Understanding left ventricular assist devices. Blood Purif 2018;46:292–300. https://doi.org/10.1159/000491872; PMID: 30048974. Callan P, Clark AL. Right heart catheterisation: indications and interpretation. Heart 2016;102:147–57. https://doi. org/10.1136/heartjnl-2015-307786; PMID: 26701966. Yang CH, Guo GBF, Yip HK, et al. Bilateral cardiac catheterizations: the safety and feasibility of a superficial forearm venous and transradial arterial approach. Int Heart J 2006;47:21–7. https://doi.org/10.1536/ihj.47.21; PMID: 16479037. Lo TS, Buch AN, Hall IR, et al. Percutaneous left and right heart catheterization in fully anticoagulated patients utilizing the radial artery and forearm vein: a two-center experience. J Interv Cardiol 2006;19:258–63. https://doi. org/10.1111/j.1540-8183.2006.00139.x; PMID: 16724969. Gilchrist IC, Kharabsheh S, Nickolaus MJ, et al. Radial approach to right heart catheterization: early experience with a promising technique. Catheter Cardiovasc Interv 2002;55:20–2. https://doi.org/10.1002/ccd.10069; PMID: 11793490. Hind D, Calvert N, McWilliams R, et al. Ultrasonic locating devices for central venous cannulation: meta-analysis. BMJ 2003;327:361. https://doi.org/10.1136/bmj.327.7411.361; PMID: 12919984.

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